Hydrogen atom addition to the surface of graphene nanoflakes: A density functional theory study

NASA Astrophysics Data System (ADS)

Tachikawa, Hiroto

2017-02-01

Polycyclic aromatic hydrocarbons (PAHs) provide a 2-dimensional (2D) reaction surface in 3-dimensional (3D) interstellar space and have been utilized as a model of graphene surfaces. In the present study, the reaction of PAHs with atomic hydrogen was investigated by means of density functional theory (DFT) to systematically elucidate the binding nature of atomic hydrogen to graphene nanoflakes. PAHs with n = 4-37 were chosen, where n indicates the number of benzene rings. Activation energies of hydrogen addition to the graphene surface were calculated to be 5.2-7.0 kcal/mol at the CAM-B3LYP/6-311G(d,p) level, which is almost constant for all PAHs. The binding energies of hydrogen atom were slightly dependent on the size (n): 14.8-28.5 kcal/mol. The absorption spectra showed that a long tail is generated at the low-energy region after hydrogen addition to the graphene surface. The electronic states of hydrogenated graphenes were discussed on the basis of theoretical results.

Structure-function mapping of BbCRASP-1, the key complement factor H and FHL-1 binding protein of Borrelia burgdorferi.

PubMed

Cordes, Frank S; Kraiczy, Peter; Roversi, Pietro; Simon, Markus M; Brade, Volker; Jahraus, Oliver; Wallis, Russell; Goodstadt, Leo; Ponting, Chris P; Skerka, Christine; Zipfel, Peter F; Wallich, Reinhard; Lea, Susan M

2006-05-01

Borrelia burgdorferi, a spirochaete transmitted to human hosts during feeding of infected Ixodes ticks, is the causative agent of Lyme disease, the most frequent vector-borne disease in Eurasia and North America. Sporadically Lyme disease develops into a chronic, multisystemic disorder. Serum-resistant B. burgdorferi strains bind complement factor H (FH) and FH-like protein 1 (FHL-1) on the spirochaete surface. This binding is dependent on the expression of proteins termed complement-regulator acquiring surface proteins (CRASPs). The atomic structure of BbCRASP-1, the key FHL-1/FH-binding protein of B. burgdorferi, has recently been determined. Our analysis indicates that its protein topology apparently evolved to provide a high affinity interaction site for FH/FHL-1 and leads to an atomic-level hypothesis for the functioning of BbCRASP-1. This work demonstrates that pathogens interact with complement regulators in ways that are distinct from the mechanisms used by the host and are thus obvious targets for drug design.

Interaction of an anticancer peptide fragment of azurin with p53 and its isolated domains studied by atomic force spectroscopy.

PubMed

Bizzarri, Anna Rita; Santini, Simona; Coppari, Emilia; Bucciantini, Monica; Di Agostino, Silvia; Yamada, Tohru; Beattie, Craig W; Cannistraro, Salvatore

2011-01-01

p28 is a 28-amino acid peptide fragment of the cupredoxin azurin derived from Pseudomonas aeruginosa that preferentially penetrates cancerous cells and arrests their proliferation in vitro and in vivo. Its antitumor activity reportedly arises from post-translational stabilization of the tumor suppressor p53 normally downregulated by the binding of several ubiquitin ligases. This would require p28 to specifically bind to p53 to inhibit specific ligases from initiating proteosome-mediated degradation. In this study, atomic force spectroscopy, a nanotechnological approach, was used to investigate the interaction of p28 with full-length p53 and its isolated domains at the single molecule level. Analysis of the unbinding forces and the dissociation rate constant suggest that p28 forms a stable complex with the DNA-binding domain of p53, inhibiting the binding of ubiquitin ligases other than Mdm2 to reduce proteasomal degradation of p53.

Interaction of an anticancer peptide fragment of azurin with p53 and its isolated domains studied by atomic force spectroscopy

PubMed Central

Bizzarri, Anna Rita; Santini, Simona; Coppari, Emilia; Bucciantini, Monica; Di Agostino, Silvia; Yamada, Tohru; Beattie, Craig W; Cannistraro, Salvatore

2011-01-01

p28 is a 28-amino acid peptide fragment of the cupredoxin azurin derived from Pseudomonas aeruginosa that preferentially penetrates cancerous cells and arrests their proliferation in vitro and in vivo. Its antitumor activity reportedly arises from post-translational stabilization of the tumor suppressor p53 normally downregulated by the binding of several ubiquitin ligases. This would require p28 to specifically bind to p53 to inhibit specific ligases from initiating proteosome-mediated degradation. In this study, atomic force spectroscopy, a nanotechnological approach, was used to investigate the interaction of p28 with full-length p53 and its isolated domains at the single molecule level. Analysis of the unbinding forces and the dissociation rate constant suggest that p28 forms a stable complex with the DNA-binding domain of p53, inhibiting the binding of ubiquitin ligases other than Mdm2 to reduce proteasomal degradation of p53. PMID:22162658

Stability of surface and subsurface hydrogen on and in Au/Ni near-surface alloys

DOE PAGES

Celik, Fuat E.; Mavrikakis, Manos

2015-01-12

Periodic, self-consistent DFT-GGA (PW91) calculations were used to study the interaction of hydrogen atoms with the (111) surfaces of substitutional near-surface alloys (NSAs) of Au and Ni with different surface layer compositions and different arrangements of Au atoms in the surface layer. The effect of hydrogen adsorption on the surface and in the first and second subsurface layers of the NSAs was studied. Increasing the Au content in the surface layer weakens hydrogen binding on the surface, but strengthens subsurface binding, suggesting that the distribution of surface and subsurface hydrogen will be different than that on pure Ni(111). While themore » metal composition of the surface layer has an effect on the binding energy of hydrogen on NSA surfaces, the local composition of the binding site has a stronger effect. For example, fcc hollow sites consisting of three Ni atoms bind H nearly as strongly as on Ni(111), and fcc sites consisting of three Au atoms bind H nearly as weakly as on Au(111). Sites with one or two Au atoms show intermediate binding energies. The preference of hydrogen for three-fold Ni hollow sites alters the relative stabilities of different surface metal atom arrangements, and may provide a driving force for adsorbate-induced surface rearrangement.« less

Stability of Surface and Subsurface Hydrogen on and in Au/Ni Near-Surface Alloys

DOE Office of Scientific and Technical Information (OSTI.GOV)

Celik, Fuat E.; Mavrikakis, Manos

2015-10-01

Periodic, self-consistent DFT-GGA (PW91) calculations were used to study the interaction of hydrogen atoms with the (111) surfaces of substitutional near-surface alloys (NSAs) of Au and Ni with different surface layer compositions and different arrangements of Au atoms in the surface layer. The effect of hydrogen adsorption on the surface and in the first and second subsurface layers of the NSAs was studied. Increasing the Au content in the surface layer weakens hydrogen binding on the surface, but strengthens subsurface binding, suggesting that the distribution of surface and subsurface hydrogen will be different than that on pure Ni(111). While themore » metal composition of the surface layer has an effect on the binding energy of hydrogen on NSA surfaces, the local composition of the binding site has a stronger effect. For example, fcc hollow sites consisting of three Ni atoms bind H nearly as strongly as on Ni(111), and fcc sites consisting of three Au atoms bind H nearly as weakly as on Au(111). Sites with one or two Au atoms show intermediate binding energies. The preference of hydrogen for three-fold Ni hollow sites alters the relative stabilities of different surface metal atom arrangements, and may provide a driving force for adsorbate-induced surface rearrangement.« less

Stability of surface and subsurface hydrogen on and in Au/Ni near-surface alloys

NASA Astrophysics Data System (ADS)

Celik, Fuat E.; Mavrikakis, Manos

2015-10-01

Periodic, self-consistent DFT-GGA (PW91) calculations were used to study the interaction of hydrogen atoms with the (111) surfaces of substitutional near-surface alloys (NSAs) of Au and Ni with different surface layer compositions and different arrangements of Au atoms in the surface layer. The effect of hydrogen adsorption on the surface and in the first and second subsurface layers of the NSAs was studied. Increasing the Au content in the surface layer weakens hydrogen binding on the surface, but strengthens subsurface binding, suggesting that the distribution of surface and subsurface hydrogen will be different than that on pure Ni(111). While the metal composition of the surface layer has an effect on the binding energy of hydrogen on NSA surfaces, the local composition of the binding site has a stronger effect. For example, fcc hollow sites consisting of three Ni atoms bind H nearly as strongly as on Ni(111), and fcc sites consisting of three Au atoms bind H nearly as weakly as on Au(111). Sites with one or two Au atoms show intermediate binding energies. The preference of hydrogen for three-fold Ni hollow sites alters the relative stabilities of different surface metal atom arrangements, and may provide a driving force for adsorbate-induced surface rearrangement.

Tight-binding tunneling amplitude of an optical lattice

NASA Astrophysics Data System (ADS)

Arzamasovs, Maksims; Liu, Bo

2017-11-01

The particle in a periodic potential is an important topic in an undergraduate quantum mechanics curriculum and a stepping stone on the way to more advanced topics, such as courses on interacting electrons in crystalline solids, and graduate-level research in solid-state and condensed matter physics. The interacting many-body phenomena are usually described in terms of the second quantized lattice Hamiltonians which treat single-particle physics on the level of tight-binding approximation and add interactions on top of it. The aim of this paper is to show how the tight-binding tunneling amplitude can be related to the strength of the periodic potential for the case of a cosine potential used in the burgeoning field of ultracold atoms. We show how to approach the problem of computing the tunneling amplitude of a deep lattice using the JWKB (Jeffreys-Wentzel-Kramers-Brillouin, also known as semiclassical) approximation. We also point out that care should be taken when applying the method of the linear combination of atomic orbitals (LCAO) in an optical lattice context. A summary of the exact solution in terms of Mathieu functions is also given.

Quantum chemistry of the minimal CdSe clusters

NASA Astrophysics Data System (ADS)

Yang, Ping; Tretiak, Sergei; Masunov, Artëm E.; Ivanov, Sergei

2008-08-01

Colloidal quantum dots are semiconductor nanocrystals (NCs) which have stimulated a great deal of research and have attracted technical interest in recent years due to their chemical stability and the tunability of photophysical properties. While internal structure of large quantum dots is similar to bulk, their surface structure and passivating role of capping ligands (surfactants) are not fully understood to date. We apply ab initio wavefunction methods, density functional theory, and semiempirical approaches to study the passivation effects of substituted phosphine and amine ligands on the minimal cluster Cd2Se2, which is also used to benchmark different computational methods versus high level ab initio techniques. Full geometry optimization of Cd2Se2 at different theory levels and ligand coverage is used to understand the affinities of various ligands and the impact of ligands on cluster structure. Most possible bonding patterns between ligands and surface Cd/Se atoms are considered, including a ligand coordinated to Se atoms. The degree of passivation of Cd and Se atoms (one or two ligands attached to one atom) is also studied. The results suggest that B3LYP/LANL2DZ level of theory is appropriate for the system modeling, whereas frequently used semiempirical methods (such as AM1 and PM3) produce unphysical results. The use of hydrogen atom for modeling of the cluster passivating ligands is found to yield unphysical results as well. Hence, the surface termination of II-VI semiconductor NCs with hydrogen atoms often used in computational models should probably be avoided. Basis set superposition error, zero-point energy, and thermal corrections, as well as solvent effects simulated with polarized continuum model are found to produce minor variations on the ligand binding energies. The effects of Cd-Se complex structure on both the electronic band gap (highest occupied molecular orbital-lowest unoccupied molecular orbital energy difference) and ligand binding energies are systematically examined. The role played by positive charges on ligand binding is also explored. The calculated binding energies for various ligands L are found to decrease in the order OPMe3>OPH3>NH2Me>=NH3>=NMe3>PMe3>PH3 for neutral clusters and OPMe3>OPH3>PMe3>=NMe3>=NH2Me>=NH3>PH3 and OPMe3>OPH3>NH2Me>=NMe3>=PMe3>=NH3>PH3 for single and double ligations of positively charged Cd2Se22+ cluster, respectively.

Enhanced nitrogen diffusion induced by atomic attrition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ochoa, E.A.; Figueroa, C.A.; Czerwiec, T.

2006-06-19

The nitrogen diffusion in steel is enhanced by previous atomic attrition with low energy xenon ions. The noble gas bombardment generates nanoscale texture surfaces and stress in the material. The atomic attrition increases nitrogen diffusion at lower temperatures than the ones normally used in standard processes. The stress causes binding energy shifts of the Xe 3d{sub 5/2} electron core level. The heavy ion bombardment control of the texture and stress of the material surfaces may be applied to several plasma processes where diffusing species are involved.

Specific interactions between DNA and regulatory protein controlled by ligand-binding: Ab initio molecular simulation

NASA Astrophysics Data System (ADS)

Matsushita, Y.; Murakawa, T.; Shimamura, K.; Oishi, M.; Ohyama, T.; Kurita, N.

2015-02-01

The catabolite activator protein (CAP) is one of the regulatory proteins controlling the transcription mechanism of gene. Biochemical experiments elucidated that the complex of CAP with cyclic AMP (cAMP) is indispensable for controlling the mechanism, while previous molecular simulations for the monomer of CAP+cAMP complex revealed the specific interactions between CAP and cAMP. However, the effect of cAMP-binding to CAP on the specific interactions between CAP and DNA is not elucidated at atomic and electronic levels. We here considered the ternary complex of CAP, cAMP and DNA in solvating water molecules and investigated the specific interactions between them at atomic and electronic levels using ab initio molecular simulations based on classical molecular dynamics and ab initio fragment molecular orbital methods. The results highlight the important amino acid residues of CAP for the interactions between CAP and cAMP and between CAP and DNA.

Calculations of the binding affinities of protein-protein complexes with the fast multipole method

NASA Astrophysics Data System (ADS)

Kim, Bongkeun; Song, Jiming; Song, Xueyu

2010-09-01

In this paper, we used a coarse-grained model at the residue level to calculate the binding free energies of three protein-protein complexes. General formulations to calculate the electrostatic binding free energy and the van der Waals free energy are presented by solving linearized Poisson-Boltzmann equations using the boundary element method in combination with the fast multipole method. The residue level model with the fast multipole method allows us to efficiently investigate how the mutations on the active site of the protein-protein interface affect the changes in binding affinities of protein complexes. Good correlations between the calculated results and the experimental ones indicate that our model can capture the dominant contributions to the protein-protein interactions. At the same time, additional effects on protein binding due to atomic details are also discussed in the context of the limitations of such a coarse-grained model.

Theoretical Studies for Dendrimer-Based Drug Delivery.

PubMed

Bello, Martiniano; Fragoso-Vázquez, Jonathan; Correa-Basurto, José

2017-01-01

Numerous theoretical studies have been performed to iteratively optimize the physicochemical properties such as dendrimer size and surface constituents in solution, as well as their molecular recognition properties for drugs, lipid membranes, nucleic acids and proteins, etc. Molecular modeling approaches such as docking and molecular dynamic (MD) simulations have supported experimental efforts by providing important insights into the structural properties of dendrimers in solution and possible binding properties of drugs at the atomic level. We review the utilization of molecular modelling tools to obtain insight into the study and design of dendrimers, with particular importance placed on the improvement of binding properties of dendrimers for their use as drug nanocarriers and to increase the water solubility properties and drug delivery. The modeling studies discussed in this review have provided substantial insight into the physicochemical properties of dendrimers in solution, including solvent pH and counterion distribution, at the atomic level, as well as the elucidation of some of the key interactions in solution of unmodified and modified dendrimers with some drugs of pharmaceutics interest and biological systems such as nucleic acids, proteins and lipid membranes. the described studies illustrate that whether simulations will be run at the all-atom or coarse-grained level, physicochemical conditions such as the type of force field, the treatment of electrostatics effects, counterion distribution, protonation state of dendrimers, and dendrimer concentrations which have been probed to play a crucial role in the structural behavior and binding properties must be prudently incorporated in the simulations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Co-Occurring Atomic Contacts for the Characterization of Protein Binding Hot Spots.

PubMed

Liu, Qian; Ren, Jing; Song, Jiangning; Li, Jinyan

2015-01-01

A binding hot spot is a small area at a protein-protein interface that can make significant contribution to binding free energy. This work investigates the substantial contribution made by some special co-occurring atomic contacts at a binding hot spot. A co-occurring atomic contact is a pair of atomic contacts that are close to each other with no more than three covalent-bond steps. We found that two kinds of co-occurring atomic contacts can play an important part in the accurate prediction of binding hot spot residues. One is the co-occurrence of two nearby hydrogen bonds. For example, mutations of any residue in a hydrogen bond network consisting of multiple co-occurring hydrogen bonds could disrupt the interaction considerably. The other kind of co-occurring atomic contact is the co-occurrence of a hydrophobic carbon contact and a contact between a hydrophobic carbon atom and a π ring. In fact, this co-occurrence signifies the collective effect of hydrophobic contacts. We also found that the B-factor measurements of several specific groups of amino acids are useful for the prediction of hot spots. Taking the B-factor, individual atomic contacts and the co-occurring contacts as features, we developed a new prediction method and thoroughly assessed its performance via cross-validation and independent dataset test. The results show that our method achieves higher prediction performance than well-known methods such as Robetta, FoldX and Hotpoint. We conclude that these contact descriptors, in particular the novel co-occurring atomic contacts, can be used to facilitate accurate and interpretable characterization of protein binding hot spots.

Co-Occurring Atomic Contacts for the Characterization of Protein Binding Hot Spots

PubMed Central

Liu, Qian; Ren, Jing; Song, Jiangning; Li, Jinyan

2015-01-01

A binding hot spot is a small area at a protein-protein interface that can make significant contribution to binding free energy. This work investigates the substantial contribution made by some special co-occurring atomic contacts at a binding hot spot. A co-occurring atomic contact is a pair of atomic contacts that are close to each other with no more than three covalent-bond steps. We found that two kinds of co-occurring atomic contacts can play an important part in the accurate prediction of binding hot spot residues. One is the co-occurrence of two nearby hydrogen bonds. For example, mutations of any residue in a hydrogen bond network consisting of multiple co-occurring hydrogen bonds could disrupt the interaction considerably. The other kind of co-occurring atomic contact is the co-occurrence of a hydrophobic carbon contact and a contact between a hydrophobic carbon atom and a π ring. In fact, this co-occurrence signifies the collective effect of hydrophobic contacts. We also found that the B-factor measurements of several specific groups of amino acids are useful for the prediction of hot spots. Taking the B-factor, individual atomic contacts and the co-occurring contacts as features, we developed a new prediction method and thoroughly assessed its performance via cross-validation and independent dataset test. The results show that our method achieves higher prediction performance than well-known methods such as Robetta, FoldX and Hotpoint. We conclude that these contact descriptors, in particular the novel co-occurring atomic contacts, can be used to facilitate accurate and interpretable characterization of protein binding hot spots. PMID:26675422

Computational Assessment of Potassium and Magnesium Ion Binding to a Buried Pocket in GTPase-Associating Center RNA

PubMed Central

2016-01-01

An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment, known as GTPase-associating center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygen atoms is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site normally include magnesium, as shown in one GAC crystal structure, another GAC crystal structure and solution experiments suggest potassium at this site. Both crystal structures also depict two magnesium ions directly bound to the phosphate groups comprising this controversial pocket. Here, we used classical molecular dynamics simulations as well as umbrella sampling to investigate the possibility of binding of potassium versus magnesium inside the pocket and to better characterize the chelation of one of the binding magnesium ions outside the pocket. The results support the preference of the pocket to accommodate potassium rather than magnesium and suggest that one of the closely binding magnesium ions can only bind at high magnesium concentrations, such as might be present during crystallization. This work illustrates the complementary utility of molecular modeling approaches with atomic-level detail in resolving discrepancies between conflicting experimental results. PMID:27983843

Computational Assessment of Potassium and Magnesium Ion Binding to a Buried Pocket in GTPase-Associating Center RNA.

PubMed

Hayatshahi, Hamed S; Roe, Daniel R; Galindo-Murillo, Rodrigo; Hall, Kathleen B; Cheatham, Thomas E

2017-01-26

An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment, known as GTPase-associating center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygen atoms is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site normally include magnesium, as shown in one GAC crystal structure, another GAC crystal structure and solution experiments suggest potassium at this site. Both crystal structures also depict two magnesium ions directly bound to the phosphate groups comprising this controversial pocket. Here, we used classical molecular dynamics simulations as well as umbrella sampling to investigate the possibility of binding of potassium versus magnesium inside the pocket and to better characterize the chelation of one of the binding magnesium ions outside the pocket. The results support the preference of the pocket to accommodate potassium rather than magnesium and suggest that one of the closely binding magnesium ions can only bind at high magnesium concentrations, such as might be present during crystallization. This work illustrates the complementary utility of molecular modeling approaches with atomic-level detail in resolving discrepancies between conflicting experimental results.

Beta Atomic Contacts: Identifying Critical Specific Contacts in Protein Binding Interfaces

PubMed Central

Liu, Qian; Kwoh, Chee Keong; Hoi, Steven C. H.

2013-01-01

Specific binding between proteins plays a crucial role in molecular functions and biological processes. Protein binding interfaces and their atomic contacts are typically defined by simple criteria, such as distance-based definitions that only use some threshold of spatial distance in previous studies. These definitions neglect the nearby atomic organization of contact atoms, and thus detect predominant contacts which are interrupted by other atoms. It is questionable whether such kinds of interrupted contacts are as important as other contacts in protein binding. To tackle this challenge, we propose a new definition called beta (β) atomic contacts. Our definition, founded on the β-skeletons in computational geometry, requires that there is no other atom in the contact spheres defined by two contact atoms; this sphere is similar to the van der Waals spheres of atoms. The statistical analysis on a large dataset shows that β contacts are only a small fraction of conventional distance-based contacts. To empirically quantify the importance of β contacts, we design βACV, an SVM classifier with β contacts as input, to classify homodimers from crystal packing. We found that our βACV is able to achieve the state-of-the-art classification performance superior to SVM classifiers with distance-based contacts as input. Our βACV also outperforms several existing methods when being evaluated on several datasets in previous works. The promising empirical performance suggests that β contacts can truly identify critical specific contacts in protein binding interfaces. β contacts thus provide a new model for more precise description of atomic organization in protein quaternary structures than distance-based contacts. PMID:23630569

Elementary Particles and Forces.

ERIC Educational Resources Information Center

Quigg, Chris

1985-01-01

Discusses subatomic particles (quarks, leptons, and others) revealed by higher accelerator energies. A connection between forces at this subatomic level has been established, and prospects are good for a description of forces that encompass binding atomic nuclei. Colors, fundamental interactions, screening, camouflage, electroweak symmetry, and…

Atomic-resolution structure of the CAP-Gly domain of dynactin on polymeric microtubules determined by magic angle spinning NMR spectroscopy.

PubMed

Yan, Si; Guo, Changmiao; Hou, Guangjin; Zhang, Huilan; Lu, Xingyu; Williams, John Charles; Polenova, Tatyana

2015-11-24

Microtubules and their associated proteins perform a broad array of essential physiological functions, including mitosis, polarization and differentiation, cell migration, and vesicle and organelle transport. As such, they have been extensively studied at multiple levels of resolution (e.g., from structural biology to cell biology). Despite these efforts, there remain significant gaps in our knowledge concerning how microtubule-binding proteins bind to microtubules, how dynamics connect different conformational states, and how these interactions and dynamics affect cellular processes. Structures of microtubule-associated proteins assembled on polymeric microtubules are not known at atomic resolution. Here, we report a structure of the cytoskeleton-associated protein glycine-rich (CAP-Gly) domain of dynactin motor on polymeric microtubules, solved by magic angle spinning NMR spectroscopy. We present the intermolecular interface of CAP-Gly with microtubules, derived by recording direct dipolar contacts between CAP-Gly and tubulin using double rotational echo double resonance (dREDOR)-filtered experiments. Our results indicate that the structure adopted by CAP-Gly varies, particularly around its loop regions, permitting its interaction with multiple binding partners and with the microtubules. To our knowledge, this study reports the first atomic-resolution structure of a microtubule-associated protein on polymeric microtubules. Our approach lays the foundation for atomic-resolution structural analysis of other microtubule-associated motors.

Alcohol-Binding Sites in Distinct Brain Proteins: The Quest for Atomic Level Resolution

PubMed Central

Howard, Rebecca J.; Slesinger, Paul A.; Davies, Daryl L.; Das, Joydip; Trudell, James R.; Harris, R. Adron

2011-01-01

Defining the sites of action of ethanol on brain proteins is a major prerequisite to understanding the molecular pharmacology of this drug. The main barrier to reaching an atomic-level understanding of alcohol action is the low potency of alcohols, ethanol in particular, which is a reflection of transient, low-affinity interactions with their targets. These mechanisms are difficult or impossible to study with traditional techniques such as radioligand binding or spectroscopy. However, there has been considerable recent progress in combining X-ray crystallography, structural modeling, and site-directed mutagenesis to define the sites and mechanisms of action of ethanol and related alcohols on key brain proteins. We review such insights for several diverse classes of proteins including inwardly rectifying potassium, transient receptor potential, and neurotransmit-ter-gated ion channels, as well as protein kinase C epsilon. Some common themes are beginning to emerge from these proteins, including hydrogen bonding of the hydroxyl group and van der Waals interactions of the methylene groups of ethanol with specific amino acid residues. The resulting binding energy is proposed to facilitate or stabilize low-energy state transitions in the bound proteins, allowing ethanol to act as a “molecular lubricant” for protein function. We discuss evidence for characteristic, discrete alcohol-binding sites on protein targets, as well as evidence that binding to some proteins is better characterized by an interaction region that can accommodate multiple molecules of ethanol. PMID:21676006

Lamb Shift of n = 1 and n = 2 States of Hydrogen-like Atoms, 1 ≤ Z ≤ 110

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yerokhin, V. A.; Shabaev, V. M.

2015-09-15

Theoretical energy levels of the n = 1 and n = 2 states of hydrogen-like atoms with the nuclear charge numbers 1 ≤ Z ≤ 110 are tabulated. The tabulation is based on ab initio quantum electrodynamics calculations performed to all orders in the nuclear binding strength parameter Zα, where α is the fine structure constant. Theoretical errors due to various effects are critically examined and estimated.

Probing the effects of surface hydrophobicity and tether orientation on antibody-antigen binding

NASA Astrophysics Data System (ADS)

Bush, Derek B.; Knotts, Thomas A.

2017-04-01

Antibody microarrays have the potential to revolutionize molecular detection for many applications, but their current use is limited by poor reliability, and efforts to change this have not yielded fruitful results. One difficulty which limits the rational engineering of next-generation devices is that little is known, at the molecular level, about the antibody-antigen binding process near solid surfaces. Atomic-level structural information is scant because typical experimental techniques (X-ray crystallography and NMR) cannot be used to image proteins bound to surfaces. To overcome this limitation, this study uses molecular simulation and an advanced, experimentally validated, coarse-grain, protein-surface model to compare fab-lysozyme binding in bulk solution and when the fab is tethered to hydrophobic and hydrophilic surfaces. The results show that the tether site in the fab, as well as the surface hydrophobicity, significantly impacts the binding process and suggests that the optimal design involves tethering fabs upright on a hydrophilic surface. The results offer an unprecedented, molecular-level picture of the binding process and give hope that the rational design of protein-microarrays is possible.

Investigating the binding behaviour of two avidin-based testosterone binders using molecular recognition force spectroscopy.

PubMed

Rangl, Martina; Leitner, Michael; Riihimäki, Tiina; Lehtonen, Soili; Hytönen, Vesa P; Gruber, Hermann J; Kulomaa, Markku; Hinterdorfer, Peter; Ebner, Andreas

2014-02-01

Molecular recognition force spectroscopy, a biosensing atomic force microscopy technique allows to characterise the dissociation of ligand-receptor complexes at the molecular level. Here, we used molecular recognition force spectroscopy to study the binding capability of recently developed testosterone binders. The two avidin-based proteins called sbAvd-1 and sbAvd-2 are expected to bind both testosterone and biotin but differ in their binding behaviour towards these ligands. To explore the ligand binding and dissociation energy landscape of these proteins, we tethered biotin or testosterone to the atomic force microscopy probe while the testosterone-binding protein was immobilized on the surface. Repeated formation and rupture of the ligand-receptor complex at different pulling velocities allowed determination of the loading rate dependence of the complex-rupturing force. In this way, we obtained the molecular dissociation rate (k(off)) and energy landscape distances (x(β)) of the four possible complexes: sbAvd-1-biotin, sbAvd-1-testosterone, sbAvd-2-biotin and sbAvd-2-testosterone. It was found that the kinetic off-rates for both proteins and both ligands are similar. In contrast, the x(β) values, as well as the probability of complex formations, varied considerably. In addition, competitive binding experiments with biotin and testosterone in solution differ significantly for the two testosterone-binding proteins, implying a decreased cross-reactivity of sbAvd-2. Unravelling the binding behaviour of the investigated testosterone-binding proteins is expected to improve their usability for possible sensing applications. Copyright © 2014 John Wiley & Sons, Ltd.

Characterization of Interactions between Heparin/Glycosaminoglycan and Adeno-associated Virus

PubMed Central

Zhang, Fuming; Aguilera, Javier; Beaudet, Julie M.; Xie, Qing; Lerch, Thomas F.; Davulcu, Omar; Colón, Wilfredo; Chapman, Michael S.; Linhardt, Robert J.

2013-01-01

Adeno-associated virus (AAV) is a key candidate in the development of gene therapy. In this report, we used surface plasmon resonance spectroscopy to study the interaction between AAV and heparin and other glycosaminoglycans. Surface plasmon resonance results revealed that heparin binds to AAV with extremely high affinity. Solution competition studies shows that AAV binding to heparin is chain length dependent. AAV prefers to bind full chain heparin. All sulfo groups (especially N-sulfo and 6-O-sulfo groups) on heparin are important for the AAV- heparin interaction. Higher levels of sulfo group substitution in GAGs enhance their binding affinities. Atomic force microscopy was also performed to image AAV-2 complexed with heparin. PMID:23952613

Mg2+ ions: do they bind to nucleobase nitrogens?

PubMed Central

Leonarski, Filip; D'Ascenzo, Luigi; Auffinger, Pascal

2017-01-01

Given the many roles proposed for Mg2+ in nucleic acids, it is essential to accurately determine their binding modes. Here, we surveyed the PDB to classify Mg2+ inner-sphere binding patterns to nucleobase imine N1/N3/N7 atoms. Among those, purine N7 atoms are considered to be the best nucleobase binding sites for divalent metals. Further, Mg2+ coordination to N7 has been implied in several ribozyme catalytic mechanisms. We report that Mg2+ assigned near imine nitrogens derive mostly from poor interpretations of electron density patterns and are most often misidentified Na+, K+, NH4+ ions, water molecules or spurious density peaks. Consequently, apart from few documented exceptions, Mg2+ ions do not bind to N7 atoms. Without much of a surprise, Mn2+, Zn2+ and Cd2+, which have a higher affinity for nitrogens, may contact N7 atoms when present in crystallization buffers. In this respect, we describe for the first time a potential Zn2+ ribosomal binding site involving two purine N7 atoms. Further, we provide a set of guidelines to help in the assignment of Mg2+ in crystallographic, cryo-EM, NMR and model building practices and discuss implications of our findings related to ion substitution experiments. PMID:27923930

Alkali (Li, K and Na) and alkali-earth (Be, Ca and Mg) adatoms on SiC single layer

NASA Astrophysics Data System (ADS)

Baierle, Rogério J.; Rupp, Caroline J.; Anversa, Jonas

2018-03-01

First-principles calculations within the density functional theory (DFT) have been addressed to study the energetic stability, and electronic properties of alkali and alkali-earth atoms adsorbed on a silicon carbide (SiC) single layer. We observe that all atoms are most stable (higher binding energy) on the top of a Si atom, which moves out of the plane (in the opposite direction to the adsorbed atom). Alkali atoms adsorbed give raise to two spin unpaired electronic levels inside the band gap leading the SiC single layer to exhibit n-type semiconductor properties. For alkaline atoms adsorbed there is a deep occupied spin paired electronic level inside the band gap. These finding suggest that the adsorption of alkaline and alkali-earth atoms on SiC layer is a powerful feature to functionalize two dimensional SiC structures, which can be used to produce new electronic, magnetic and optical devices as well for hydrogen and oxygen evolution reaction (HER and OER, respectively). Furthermore, we observe that the adsorption of H2 is ruled by dispersive forces (van der Waals interactions) while the O2 molecule is strongly adsorbed on the functionalized system.

SCOWLP classification: Structural comparison and analysis of protein binding regions

PubMed Central

Teyra, Joan; Paszkowski-Rogacz, Maciej; Anders, Gerd; Pisabarro, M Teresa

2008-01-01

Background Detailed information about protein interactions is critical for our understanding of the principles governing protein recognition mechanisms. The structures of many proteins have been experimentally determined in complex with different ligands bound either in the same or different binding regions. Thus, the structural interactome requires the development of tools to classify protein binding regions. A proper classification may provide a general view of the regions that a protein uses to bind others and also facilitate a detailed comparative analysis of the interacting information for specific protein binding regions at atomic level. Such classification might be of potential use for deciphering protein interaction networks, understanding protein function, rational engineering and design. Description Protein binding regions (PBRs) might be ideally described as well-defined separated regions that share no interacting residues one another. However, PBRs are often irregular, discontinuous and can share a wide range of interacting residues among them. The criteria to define an individual binding region can be often arbitrary and may differ from other binding regions within a protein family. Therefore, the rational behind protein interface classification should aim to fulfil the requirements of the analysis to be performed. We extract detailed interaction information of protein domains, peptides and interfacial solvent from the SCOWLP database and we classify the PBRs of each domain family. For this purpose, we define a similarity index based on the overlapping of interacting residues mapped in pair-wise structural alignments. We perform our classification with agglomerative hierarchical clustering using the complete-linkage method. Our classification is calculated at different similarity cut-offs to allow flexibility in the analysis of PBRs, feature especially interesting for those protein families with conflictive binding regions. The hierarchical classification of PBRs is implemented into the SCOWLP database and extends the SCOP classification with three additional family sub-levels: Binding Region, Interface and Contacting Domains. SCOWLP contains 9,334 binding regions distributed within 2,561 families. In 65% of the cases we observe families containing more than one binding region. Besides, 22% of the regions are forming complex with more than one different protein family. Conclusion The current SCOWLP classification and its web application represent a framework for the study of protein interfaces and comparative analysis of protein family binding regions. This comparison can be performed at atomic level and allows the user to study interactome conservation and variability. The new SCOWLP classification may be of great utility for reconstruction of protein complexes, understanding protein networks and ligand design. SCOWLP will be updated with every SCOP release. The web application is available at . PMID:18182098

Role of halogen and hydrogen bonds for stabilization of antithyroid drugs with hypohalous acids (HOX, X = I, Br, and Cl) adducts

NASA Astrophysics Data System (ADS)

El-Sheshtawy, Hamdy S.; El-Mehasseb, Ibrahim

2017-11-01

The mechanism for the inhibition of thyroid hormones by the thioamide-like antithyroid drug is a key process in the thyroid gland function. Therefore, in this study theoretical investigation of the molecular interaction between two antithyroid drugs, namely methimazol (MMI) and thiazoline-2-thione (T2T), with the hypohalous acids (HOX, X = I, Br, and Cl), which act as heme-linked halogenated species to tyrosine residue was discussed. The calculations were performed by M06-2X and MP2 using aug-cc-pVDZ level of theory. In addition, wB97xd/6-31G* level of theory was used in order to account for the dispersion forces. The results show the possible formation of three adducts, which is stabilized by halogen bond (I), both halogen and hydrogen bonds (II), two hydrogen bonds (III). The binding energies of the complexes reveals stabilization in the order III > II > I. The binding energies of the complexes was increased with increasing the electron affinity and polarizability of halogen atom, the dipole moment of the complexes (I and II), the electrostatic potential on halogen atom (Vmax:i.e σ-hole), and the charge-transfer process through the halogen bond in I. On the other hand, the binding energies of the complexes decreased with increasing the halogen atom electronegativity and the dipole moment of complex III. Natural bond orbital (NBO) analysis was used to investigate the molecular orbital interactions and the charge transfer process upon complexation.

Degradation of Perfluorinated Ether Lubricants on Pure Aluminum Surfaces: Semiempirical Quantum Chemical Modeling

NASA Technical Reports Server (NTRS)

Slaby, Scott M.; Ewing, David W.; Zehe, Michael J.

1997-01-01

The AM1 semiempirical quantum chemical method was used to model the interaction of perfluoroethers with aluminum surfaces. Perfluorodimethoxymethane and perfluorodimethyl ether were studied interacting with aluminum surfaces, which were modeled by a five-atom cluster and a nine-atom cluster. Interactions were studied for edge (high index) sites and top (low index) sites of the clusters. Both dissociative binding and nondissociative binding were found, with dissociative binding being stronger. The two different ethers bound and dissociated on the clusters in different ways: perfluorodimethoxymethane through its oxygen atoms, but perfluorodimethyl ether through its fluorine atoms. The acetal linkage of perfluorodimeth-oxymethane was the key structural feature of this molecule in its binding and dissociation on the aluminum surface models. The high-index sites of the clusters caused the dissociation of both ethers. These results are consistent with the experimental observation that perfluorinated ethers decompose in contact with sputtered aluminum surfaces.

Magnetic anisotropy of heteronuclear dimers in the gas phase and supported on graphene: relativistic density-functional calculations.

PubMed

Błoński, Piotr; Hafner, Jürgen

2014-04-09

The structural and magnetic properties of mixed PtCo, PtFe, and IrCo dimers in the gas phase and supported on a free-standing graphene layer have been calculated using density-functional theory, both in the scalar-relativistic limit and self-consistently including spin-orbit coupling. The influence of the strong magnetic moments of the 3d atoms on the spin and orbital moments of the 5d atoms, and the influence of the strong spin-orbit coupling contributed by the 5d atom on the orbital moments of the 3d atoms have been studied in detail. The magnetic anisotropy energy is found to depend very sensitively on the nature of the eigenstates in the vicinity of the Fermi level, as determined by band filling, exchange splitting and spin-orbit coupling. The large magnetic anisotropy energy of free PtCo and IrCo dimers relative to the easy direction parallel to the dimer axis is coupled to a strong anisotropy of the orbital magnetic moments of the Co atom for both dimers, and also on the Ir atom in IrCo. In contrast the PtFe dimer shows a weak perpendicular anisotropy and only small spin and orbital anisotropies of opposite sign on the two atoms. For dimers supported on graphene, the strong binding within the dimer and the stronger interaction of the 3d atom with the substrate stabilizes an upright geometry. Spin and orbital moments on the 3d atom are strongly quenched, but due to the weaker binding within the dimer the properties of the 5d atom are more free-atom-like with increased spin and orbital moments. The changes in the magnetic moment are reflected in the structure of the electronic eigenstates near the Fermi level, for all three dimers the easy magnetic direction is now parallel to the dimer axis and perpendicular to the graphene layer. The already very large magnetic anisotropy energy (MAE) of IrCo is further enhanced by the interaction with the support, the MAE of PtFe changes sign, and that of the PtCo dimer is reduced. These changes are discussed in relation to the relativistic electronic structure of free and supported dimers and it is demonstrated that the existence of a partially occupied quasi-degenerate state at the Fermi level favors the formation of a large magnetic anisotropy.

Factors driving stable growth of He clusters in W: first-principles study

NASA Astrophysics Data System (ADS)

Feng, Y. J.; Xin, T. Y.; Xu, Q.; Wang, Y. X.

2018-07-01

The evolution of helium (He) bubbles is responsible for the surface morphology variation and subsequent degradation of the properties of plasma-facing materials (PFMs) in nuclear fusion reactors. These severe problems unquestionably trace back to the behavior of He in PFMs, which is closely associated with the interaction between He and the matrix. In this paper, we decomposed the binding energy of the He cluster into three parts, those from W–W, W–He, and He–He interactions, using density functional theory. As a result, we clearly identified the main factors that determine a steplike decrease in the binding energy with increasing number of He atoms, which explains the process of self-trapping and athermal vacancy generation during He cluster growth in the PFM tungsten. The three interactions were found to synergetically shape the features of the steplike decrease in the binding energy. Fairly strong He–He repulsive forces at a short distance, which stem from antibonding states between He atoms, need to be released when additional He atoms are continuously bonded to the He cluster. This causes the steplike feature in the binding energy. The bonding states between W and He atoms in principle facilitate the decreasing trend of the binding energy. The decrease in binding energy with increasing number of He atoms implies that He clusters can grow stably.

Crystallization and preliminary X-ray crystallographic analysis of BxlE, a xylobiose transporter from Streptomyces thermoviolaceus OPC-520

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seike, Kiho; Sato, Junji; Tomoo, Koji, E-mail: tomoo@gly.oups.ac.jp

2007-07-01

To clarify the structural basis of sugar binding by BxlE at the atomic level, recombinant BxlE was crystallized using the hanging-drop vapour-diffusion method at 290 K. Together with the integral membrane proteins BxlF and BxlG, BxlE isolated from Streptomyces thermoviolaceus OPC-520 forms an ATP-binding cassette (ABC) transport system that mediates the uptake of xylan. To clarify the structural basis of sugar binding by BxlE at the atomic level, recombinant BxlE was crystallized using the hanging-drop vapour-diffusion method at 290 K. The crystals belonged to the monoclinic space group P2{sub 1}, with unit-cell parameters a = 44.63, b = 63.27, cmore » = 66.40 Å, β = 103.05°, and contained one 48 kDa molecule per asymmetric unit (V{sub M} = 1.96 Å{sup 3} Da{sup −1}). Diffraction data collected to a resolution of 1.65 Å using a rotating-anode X-ray source gave a data set with an overall R{sub merge} of 2.6% and a completeness of 91.3%. A data set from a platinum derivative is being used for phasing by the SAD method.« less

Stability chart of small mixed 4He-3He clusters

NASA Astrophysics Data System (ADS)

Guardiola, R.; Navarro, J.

2003-11-01

A stability chart of mixed 4He and 3He clusters has been obtained by means of the diffusion Monte Carlo method, using both the Aziz HFD-B and the Tang-Toennies-Yiu atom-atom interaction. The investigated clusters contain up to eight 4He atoms and up to 20 3He atoms. One single 4He binds 20 3He atoms, and two 4He bind 1, 2, 8, and more than 14 3He atoms. All clusters with three or more 4He atoms are bound, although the combinations 4He33He9,10,11 and 4He34He9 are metastable. Clusters with 2, 8, and 20 3He atoms are particularly stable and define magic 3He numbers.

Site Identification by Ligand Competitive Saturation (SILCS) simulations for fragment-based drug design.

PubMed

Faller, Christina E; Raman, E Prabhu; MacKerell, Alexander D; Guvench, Olgun

2015-01-01

Fragment-based drug design (FBDD) involves screening low molecular weight molecules ("fragments") that correspond to functional groups found in larger drug-like molecules to determine their binding to target proteins or nucleic acids. Based on the principle of thermodynamic additivity, two fragments that bind nonoverlapping nearby sites on the target can be combined to yield a new molecule whose binding free energy is the sum of those of the fragments. Experimental FBDD approaches, like NMR and X-ray crystallography, have proven very useful but can be expensive in terms of time, materials, and labor. Accordingly, a variety of computational FBDD approaches have been developed that provide different levels of detail and accuracy.The Site Identification by Ligand Competitive Saturation (SILCS) method of computational FBDD uses all-atom explicit-solvent molecular dynamics (MD) simulations to identify fragment binding. The target is "soaked" in an aqueous solution with multiple fragments having different identities. The resulting computational competition assay reveals what small molecule types are most likely to bind which regions of the target. From SILCS simulations, 3D probability maps of fragment binding called "FragMaps" can be produced. Based on the probabilities relative to bulk, SILCS FragMaps can be used to determine "Grid Free Energies (GFEs)," which provide per-atom contributions to fragment binding affinities. For essentially no additional computational overhead relative to the production of the FragMaps, GFEs can be used to compute Ligand Grid Free Energies (LGFEs) for arbitrarily complex molecules, and these LGFEs can be used to rank-order the molecules in accordance with binding affinities.

First-principles study of the binding energy between nanostructures and its scaling with system size

NASA Astrophysics Data System (ADS)

Tao, Jianmin; Jiao, Yang; Mo, Yuxiang; Yang, Zeng-Hui; Zhu, Jian-Xin; Hyldgaard, Per; Perdew, John P.

2018-04-01

The equilibrium van der Waals binding energy is an important factor in the design of materials and devices. However, it presents great computational challenges for materials built up from nanostructures. Here we investigate the binding-energy scaling behavior from first-principles calculations. We show that the equilibrium binding energy per atom between identical nanostructures can scale up or down with nanostructure size, but can be parametrized for large N with an analytical formula (in meV/atom), Eb/N =a +b /N +c /N2+d /N3 , where N is the number of atoms in a nanostructure and a , b , c , and d are fitting parameters, depending on the properties of a nanostructure. The formula is consistent with a finite large-size limit of binding energy per atom. We find that there are two competing factors in the determination of the binding energy: Nonadditivities of van der Waals coefficients and center-to-center distance between nanostructures. To decode the detail, the nonadditivity of the static multipole polarizability is investigated from an accurate spherical-shell model. We find that the higher-order multipole polarizability displays ultrastrong intrinsic nonadditivity, no matter if the dipole polarizability is additive or not.

Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug.

PubMed

Rand, Jacob H; Wu, Xiao-Xuan; Quinn, Anthony S; Ashton, Anthony W; Chen, Pojen P; Hathcock, James J; Andree, Harry A M; Taatjes, Douglas J

2010-03-18

Annexin A5 (AnxA5) is a potent anticoagulant protein that crystallizes over phospholipid bilayers (PLBs), blocking their availability for coagulation reactions. Antiphospholipid antibodies disrupt AnxA5 binding, thereby accelerating coagulation reactions. This disruption may contribute to thrombosis and miscarriages in the antiphospholipid syndrome (APS). We investigated whether the antimalarial drug, hydroxychloroquine (HCQ), might affect this prothrombotic mechanism. Binding of AnxA5 to PLBs was measured with labeled AnxA5 and also imaged with atomic force microscopy. Immunoglobulin G levels, AnxA5, and plasma coagulation times were measured on cultured human umbilical vein endothelial cells and a syncytialized trophoblast cell line. AnxA5 anticoagulant activities of APS patient plasmas were also determined. HCQ reversed the effect of antiphospholipid antibodies on AnxA5 and restored AnxA5 binding to PLBs, an effect corroborated by atomic force microscopy. Similar reversals of antiphospholipid-induced abnormalities were measured on the surfaces of human umbilical vein endothelial cells and syncytialized trophoblast cell lines, wherein HCQ reduced the binding of antiphospholipid antibodies, increased cell-surface AnxA5 concentrations, and prolonged plasma coagulation to control levels. In addition, HCQ increased the AnxA5 anticoagulant activities of APS patient plasmas. In conclusion, HCQ reversed antiphospholipid-mediated disruptions of AnxA5 on PLBs and cultured cells, and in APS patient plasmas. These results support the concept of novel therapeutic approaches that address specific APS disease mechanisms.

Quantum Degeneracy in Atomic Point Contacts Revealed by Chemical Force and Conductance

NASA Astrophysics Data System (ADS)

Sugimoto, Yoshiaki; Ondráček, Martin; Abe, Masayuki; Pou, Pablo; Morita, Seizo; Perez, Ruben; Flores, Fernando; Jelínek, Pavel

2013-09-01

Quantum degeneracy is an important concept in quantum mechanics with large implications to many processes in condensed matter. Here, we show the consequences of electron energy level degeneracy on the conductance and the chemical force between two bodies at the atomic scale. We propose a novel way in which a scanning probe microscope can detect the presence of degenerate states in atomic-sized contacts even at room temperature. The tunneling conductance G and chemical binding force F between two bodies both tend to decay exponentially with distance in a certain distance range, usually maintaining direct proportionality G∝F. However, we show that a square relation G∝F2 arises as a consequence of quantum degeneracy between the interacting frontier states of the scanning tip and a surface atom. We demonstrate this phenomenon on the Si(111)-(7×7) surface reconstruction where the Si adatom possesses a strongly localized dangling-bond state at the Fermi level.

Crown oxygen-doping graphene with embedded main-group metal atoms

NASA Astrophysics Data System (ADS)

Wu, Liyuan; Wang, Qian; Yang, Chuanghua; Quhe, Ruge; Guan, Pengfei; Lu, Pengfei

2018-02-01

Different main-group metal atoms embedded in crown oxygen-doping graphene (metal@OG) systems are studied by the density functional theory. The binding energies and electronic structures are calculated by using first-principles calculations. The binding energy of metal@OG system mainly depends on the electronegativity of the metal atom. The lower the value of the electronegativity, the larger the binding energy, indicating the more stable the system. The electronic structure of metal@OG arouses the emergence of bandgap and shift of Dirac point. It is shown that interaction between metal atom and crown oxygen-doping graphene leads to the graphene's stable n-doping, and the metal@OG systems are stable semiconducting materials, which can be used in technological applications.

Application of the Interacting Quantum Atoms Approach to the S66 and Ionic-Hydrogen-Bond Datasets for Noncovalent Interactions.

PubMed

Suárez, Dimas; Díaz, Natalia; Francisco, Evelio; Martín Pendás, Angel

2018-04-17

The interacting quantum atoms (IQA) method can assess, systematically and in great detail, the strength and physics of both covalent and noncovalent interactions. The lack of a pair density in density functional theory (DFT), which precludes the direct IQA decomposition of the characteristic exchange-correlation energy, has been recently overcome by means of a scaling technique, which can largely expand the applicability of the method. To better assess the utility of the augmented IQA methodology to derive quantum chemical decompositions at the atomic and molecular levels, we report the results of Hartree-Fock (HF) and DFT calculations on the complexes included in the S66 and the ionic H-bond databases of benchmark geometry and binding energies. For all structures, we perform single-point and geometry optimizations using HF and selected DFT methods with triple-ζ basis sets followed by full IQA calculations. Pairwise dispersion energies are accounted for by the D3 method. We analyze the goodness of the HF-D3 and DFT-D3 binding energies, the magnitude of numerical errors, the fragment and atomic distribution of formation energies, etc. It is shown that fragment-based IQA decomposes the formation energies in comparable terms to those of perturbative approaches and that the atomic IQA energies hold the promise of rigorously quantifying atomic and group energy contributions in larger biomolecular systems. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Reactivity and Catalytic Activity of Hydrogen Atom Chemisorbed Silver Clusters.

PubMed

Manzoor, Dar; Pal, Sourav

2015-06-18

Metal clusters of silver have attracted recent interest of researchers as a result of their potential in different catalytic applications and low cost. However, due to the completely filled d orbital and very high first ionization potential of the silver atom, the silver-based catalysts interact very weakly with the reacting molecules. In the current work, density functional theory calculations were carried out to investigate the effect of hydrogen atom chemisorption on the reactivity and catalytic properties of inert silver clusters. Our results affirm that the hydrogen atom chemisorption leads to enhancement in the binding energy of the adsorbed O2 molecule on the inert silver clusters. The increase in the binding energy is also characterized by the decrease in the Ag-O and increase in the O-O bond lengths in the case of the AgnH silver clusters. Pertinent to the increase in the O-O bond length, a significant red shift in the O-O stretching frequency is also noted in the case of the AgnH silver clusters. Moreover, the hydrogen atom chemisorbed silver clusters show low reaction barriers and high heat of formation of the final products for the environmentally important CO oxidation reaction as compared to the parent catalytically inactive clusters. The obtained results were compared with those of the corresponding gold and hydrogen atom chemisorbed gold clusters obtained at the same level of theory. It is expected the current computational study will provide key insights for future advances in the design of efficient nanosilver-based catalysts through the adsorption of a small atom or a ligand.

Unusual structures of MgF5- superhalogen anion

NASA Astrophysics Data System (ADS)

Anusiewicz, Iwona; Skurski, Piotr

2007-05-01

The vertical electron detachment energies (VDE) of three MgF5- anions were calculated at the outer valence Green function level with the 6-311 + G(3df) basis sets. This species was found to form unusual geometrical structures each of which corresponds to an anionic state exhibiting superhalogen nature. The global minimum structure was described as a system in which two central magnesium atoms are linked via symmetrical triangle formed by three fluorine atoms. Extremely large electron binding energies of these anions (exceeding 8.5 eV in all cases) were predicted and discussed.

Nonlocal torque operators in ab initio theory of the Gilbert damping in random ferromagnetic alloys

NASA Astrophysics Data System (ADS)

Turek, I.; Kudrnovský, J.; Drchal, V.

2015-12-01

We present an ab initio theory of the Gilbert damping in substitutionally disordered ferromagnetic alloys. The theory rests on introduced nonlocal torques which replace traditional local torque operators in the well-known torque-correlation formula and which can be formulated within the atomic-sphere approximation. The formalism is sketched in a simple tight-binding model and worked out in detail in the relativistic tight-binding linear muffin-tin orbital method and the coherent potential approximation (CPA). The resulting nonlocal torques are represented by nonrandom, non-site-diagonal, and spin-independent matrices, which simplifies the configuration averaging. The CPA-vertex corrections play a crucial role for the internal consistency of the theory and for its exact equivalence to other first-principles approaches based on the random local torques. This equivalence is also illustrated by the calculated Gilbert damping parameters for binary NiFe and FeCo random alloys, for pure iron with a model atomic-level disorder, and for stoichiometric FePt alloys with a varying degree of L 10 atomic long-range order.

Extended Fenske-Hall LCAO MO calculations of core-level shifts in solid P compounds

NASA Astrophysics Data System (ADS)

Franke, R.; Chassé, T.; Reinhold, J.; Streubel, P.; Szargan, R.

1997-08-01

Extended Fenske-Hall LCAO-MO ΔSCF calculations on solids modelled as H-pseudoatom saturated clusters are reported. The computational results verify the experimentally obtained initial-state (effective atomic charges, Madelung potential) and relaxation-energy contributions to the XPS phosphorus core-level binding energy shifts measured in Na 3PO 3S, Na 3PO 4, Na 2PO 3F and NH 4PF 6 in reference to red phosphorus. It is shown that the different initial-state contributions observed in the studied phosphates are determined by local and nonlocal terms while the relaxation-energy contributions are mainly dependent on the nature of the nearest neighbors of the phosphorus atom.

Estimating Atomic Contributions to Hydration and Binding Using Free Energy Perturbation.

PubMed

Irwin, Benedict W J; Huggins, David J

2018-06-12

We present a general method called atom-wise free energy perturbation (AFEP), which extends a conventional molecular dynamics free energy perturbation (FEP) simulation to give the contribution to a free energy change from each atom. AFEP is derived from an expansion of the Zwanzig equation used in the exponential averaging method by defining that the system total energy can be partitioned into contributions from each atom. A partitioning method is assumed and used to group terms in the expansion to correspond to individual atoms. AFEP is applied to six example free energy changes to demonstrate the method. Firstly, the hydration free energies of methane, methanol, methylamine, methanethiol, and caffeine in water. AFEP highlights the atoms in the molecules that interact favorably or unfavorably with water. Finally AFEP is applied to the binding free energy of human immunodeficiency virus type 1 protease to lopinavir, and AFEP reveals the contribution of each atom to the binding free energy, indicating candidate areas of the molecule to improve to produce a more strongly binding inhibitor. FEP gives a single value for the free energy change and is already a very useful method. AFEP gives a free energy change for each "part" of the system being simulated, where part can mean individual atoms, chemical groups, amino acids, or larger partitions depending on what the user is trying to measure. This method should have various applications in molecular dynamics studies of physical, chemical, or biochemical phenomena, specifically in the field of computational drug discovery.

Atomic-Level Structural Dynamics of Polyoxoniobates during DMMP Decomposition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Qi; Chapleski, Robert C.; Plonka, Anna M.

Ambient pressure in situ synchrotron-based spectroscopic techniques have been correlated to illuminate atomic-level details of bond breaking and formation during the hydrolysis of a chemical warfare nerve agent simulant over a polyoxometalate catalyst. Specifically, a Cs 8[Nb 6O 19] polyoxoniobate catalyst has been shown to react readily with dimethyl methylphosphonate (DMMP). The atomic-level transformations of all reactant moieties, the [Nb 6O 19] 8- polyanion, its Cs + counterions, and the DMMP substrate, were tracked under ambient conditions by a combination of X-ray absorption fine structure spectroscopy, Raman spectroscopy, and X-ray diffraction. Results reveal that the reaction mechanism follows general basemore » (in contrast to specific base) hydrolysis. Together with computational results, the work demonstrates that the ultimate fate of DMMP hydrolysis at the Cs 8[Nb 6O 19] catalyst is strong binding of the (methyl) methylphosphonic acid ((M)MPA) product to the polyanions, which ultimately inhibits catalytic turnover.« less

Atomic-Level Structural Dynamics of Polyoxoniobates during DMMP Decomposition

DOE PAGES

Wang, Qi; Chapleski, Robert C.; Plonka, Anna M.; ...

2017-04-10

Ambient pressure in situ synchrotron-based spectroscopic techniques have been correlated to illuminate atomic-level details of bond breaking and formation during the hydrolysis of a chemical warfare nerve agent simulant over a polyoxometalate catalyst. Specifically, a Cs 8[Nb 6O 19] polyoxoniobate catalyst has been shown to react readily with dimethyl methylphosphonate (DMMP). The atomic-level transformations of all reactant moieties, the [Nb 6O 19] 8- polyanion, its Cs + counterions, and the DMMP substrate, were tracked under ambient conditions by a combination of X-ray absorption fine structure spectroscopy, Raman spectroscopy, and X-ray diffraction. Results reveal that the reaction mechanism follows general basemore » (in contrast to specific base) hydrolysis. Together with computational results, the work demonstrates that the ultimate fate of DMMP hydrolysis at the Cs 8[Nb 6O 19] catalyst is strong binding of the (methyl) methylphosphonic acid ((M)MPA) product to the polyanions, which ultimately inhibits catalytic turnover.« less

The complex nature of calcium cation interactions with phospholipid bilayers

PubMed Central

Melcrová, Adéla; Pokorna, Sarka; Pullanchery, Saranya; Kohagen, Miriam; Jurkiewicz, Piotr; Hof, Martin; Jungwirth, Pavel; Cremer, Paul S.; Cwiklik, Lukasz

2016-01-01

Understanding interactions of calcium with lipid membranes at the molecular level is of great importance in light of their involvement in calcium signaling, association of proteins with cellular membranes, and membrane fusion. We quantify these interactions in detail by employing a combination of spectroscopic methods with atomistic molecular dynamics simulations. Namely, time-resolved fluorescent spectroscopy of lipid vesicles and vibrational sum frequency spectroscopy of lipid monolayers are used to characterize local binding sites of calcium in zwitterionic and anionic model lipid assemblies, while dynamic light scattering and zeta potential measurements are employed for macroscopic characterization of lipid vesicles in calcium-containing environments. To gain additional atomic-level information, the experiments are complemented by molecular simulations that utilize an accurate force field for calcium ions with scaled charges effectively accounting for electronic polarization effects. We demonstrate that lipid membranes have substantial calcium-binding capacity, with several types of binding sites present. Significantly, the binding mode depends on calcium concentration with important implications for calcium buffering, synaptic plasticity, and protein-membrane association. PMID:27905555

The complex nature of calcium cation interactions with phospholipid bilayers

NASA Astrophysics Data System (ADS)

Melcrová, Adéla; Pokorna, Sarka; Pullanchery, Saranya; Kohagen, Miriam; Jurkiewicz, Piotr; Hof, Martin; Jungwirth, Pavel; Cremer, Paul S.; Cwiklik, Lukasz

2016-12-01

Understanding interactions of calcium with lipid membranes at the molecular level is of great importance in light of their involvement in calcium signaling, association of proteins with cellular membranes, and membrane fusion. We quantify these interactions in detail by employing a combination of spectroscopic methods with atomistic molecular dynamics simulations. Namely, time-resolved fluorescent spectroscopy of lipid vesicles and vibrational sum frequency spectroscopy of lipid monolayers are used to characterize local binding sites of calcium in zwitterionic and anionic model lipid assemblies, while dynamic light scattering and zeta potential measurements are employed for macroscopic characterization of lipid vesicles in calcium-containing environments. To gain additional atomic-level information, the experiments are complemented by molecular simulations that utilize an accurate force field for calcium ions with scaled charges effectively accounting for electronic polarization effects. We demonstrate that lipid membranes have substantial calcium-binding capacity, with several types of binding sites present. Significantly, the binding mode depends on calcium concentration with important implications for calcium buffering, synaptic plasticity, and protein-membrane association.

Detection of a Fermi-level crossing in Si(557)-Au with inverse photoemission

NASA Astrophysics Data System (ADS)

Lipton-Duffin, J. A.; MacLeod, J. M.; McLean, A. B.

2006-06-01

The unoccupied energy bands of the quasi-one-dimensional (1D) Si(557)-Au system have been studied with momentum-resolved inverse photoemission. A band is found that lies (0.4±0.4)eV above the Fermi level at the center of the surface Brillouin zone (Γ¯) . It disperses to higher binding energy, along the Γ Kmacr direction, and crosses the Fermi level at k‖=0.5±0.1Å-1 . The corresponding direction in real space is parallel to both the rows of silicon adatoms and the rows of embedded gold atoms that are distinctive features of this surface reconstruction. The location of the crossing is in good agreement with previously published photoemission data [Altmann , Phys. Rev. B 64, 035406 (2001); Ahn , Phys. Rev. Lett. 91, 196403 (2003)], where two closely spaced bands were found to disperse from the Kmacr zone boundary to lower binding energy and then cross the Fermi level. In addition to the band mentioned above, a band was found that has parabolic dispersion along Γ Kmacr , the direction that is parallel to the rows of embedded gold atoms. The band minimum for the parabolic band lies (0.8±0.4)eV below the vacuum level and it has an effective mass m*=(1.0±0.1)me , where me is the free electron mass. Perpendicular to the rows of gold atoms, as expected for a state with quasi-1D symmetry, it has flat dispersion. This band may be an image state resonance, overlapping the silicon conduction band continuum, and it is spatially localized to the edge of the silicon terraces.

Iodine Atoms: A New Molecular Feature for the Design of Potent Transthyretin Fibrillogenesis Inhibitors

PubMed Central

Pinto, Marta; Almeida, Maria Rosário; Gales, Luis; Ballesteros, Alfredo; Barluenga, José; Pérez, Juan J.; Vázquez, Jesús T.; Centeno, Nuria B.; Saraiva, Maria Joao; Damas, Ana M.; Planas, Antoni; Arsequell, Gemma; Valencia, Gregorio

2009-01-01

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis. PMID:19125186

Nanodisc-Targeted STD NMR Spectroscopy Reveals Atomic Details of Ligand Binding to Lipid Environments.

PubMed

Muñoz-García, Juan C; Inacio Dos Reis, Rosana; Taylor, Richard J; Henry, Alistair J; Watts, Anthony

2018-05-18

Saturation transfer difference (STD) NMR spectroscopy is one of the most popular ligand-based NMR techniques for the study of protein-ligand interactions. This is due to its robustness and the fact that it is focused on the signals of the ligand, without any need for NMR information on the macromolecular target. This technique is most commonly applied to systems involving different types of ligands (e.g., small organic molecules, carbohydrates or lipids) and a protein as the target, in which the latter is selectively saturated. However, only a few examples have been reported where membrane mimetics are the macromolecular binding partners. Here, we have employed STD NMR spectroscopy to investigate the interactions of the neurotransmitter dopamine with mimetics of lipid bilayers, such as nanodiscs, by saturation of the latter. In particular, the interactions between dopamine and model lipid nanodiscs formed either from charged or zwitterionic lipids have been resolved at the atomic level. The results, in agreement with previous isothermal titration calorimetry studies, show that dopamine preferentially binds to negatively charged model membranes, but also provide detailed atomic insights into the mode of interaction of dopamine with membrane mimetics. Our findings provide relevant structural information for the design of lipid-based drug carriers of dopamine and its structural analogues and are of general applicability to other systems. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations

PubMed Central

Marino, Kristen A.; Filizola, Marta

2017-01-01

An increasing number of G protein-coupled receptor (GPCR) crystal structures provide important—albeit static—pictures of how small molecules or peptides interact with their receptors. These high-resolution structures represent a tremendous opportunity to apply molecular dynamics (MD) simulations to capture atomic-level dynamical information that is not easy to obtain experimentally. Understanding ligand binding and unbinding processes, as well as the related responses of the receptor, is crucial to the design of better drugs targeting GPCRs. Here, we discuss possible ways to study the dynamics involved in the binding of small molecules to GPCRs, using long timescale MD simulations or metadynamics-based approaches. PMID:29188572

Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations.

PubMed

Marino, Kristen A; Filizola, Marta

2018-01-01

An increasing number of G protein-coupled receptor (GPCR) crystal structures provide important-albeit static-pictures of how small molecules or peptides interact with their receptors. These high-resolution structures represent a tremendous opportunity to apply molecular dynamics (MD) simulations to capture atomic-level dynamical information that is not easy to obtain experimentally. Understanding ligand binding and unbinding processes, as well as the related responses of the receptor, is crucial to the design of better drugs targeting GPCRs. Here, we discuss possible ways to study the dynamics involved in the binding of small molecules to GPCRs, using long timescale MD simulations or metadynamics-based approaches.

Interaction between Pin1 and its natural product inhibitor epigallocatechin-3-gallate by spectroscopy and molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Xi, Lei; Wang, Yu; He, Qing; Zhang, Qingyan; Du, Linfang

2016-12-01

The binding of epigallocatechin-3-gallate (EGCG) to wild type Pin1 in solution was studied by spectroscopic methods and molecular dynamics simulations in this research to explore the binding mode and inhibition mechanism. The binding constants and number of binding sites per Pin1 for EGCG were calculated through the Stern-Volmer equation. The values of binding free energy and thermodynamic parameters were calculated and indicated that hydrogen bonds, electrostatic interaction and Van der Waals interaction played the major role in the binding process. The alterations of Pin1 secondary structure in the presence of EGCG were confirmed by far-UV circular dichroism spectra. The binding model at atomic-level revealed that EGCG was bound to the Glu12, Lys13, Arg14, Met15 and Arg17 in WW domain. Furthermore, EGCG could also interact with Arg69, Asp112, Cys113 and Ser114 in PPIase domain.

A simple atomic-level hydrophobicity scale reveals protein interfacial structure.

PubMed

Kapcha, Lauren H; Rossky, Peter J

2014-01-23

Many amino acid residue hydrophobicity scales have been created in an effort to better understand and rapidly characterize water-protein interactions based only on protein structure and sequence. There is surprisingly low consistency in the ranking of residue hydrophobicity between scales, and their ability to provide insightful characterization varies substantially across subject proteins. All current scales characterize hydrophobicity based on entire amino acid residue units. We introduce a simple binary but atomic-level hydrophobicity scale that allows for the classification of polar and non-polar moieties within single residues, including backbone atoms. This simple scale is first shown to capture the anticipated hydrophobic character for those whole residues that align in classification among most scales. Examination of a set of protein binding interfaces establishes good agreement between residue-based and atomic-level descriptions of hydrophobicity for five residues, while the remaining residues produce discrepancies. We then show that the atomistic scale properly classifies the hydrophobicity of functionally important regions where residue-based scales fail. To illustrate the utility of the new approach, we show that the atomic-level scale rationalizes the hydration of two hydrophobic pockets and the presence of a void in a third pocket within a single protein and that it appropriately classifies all of the functionally important hydrophilic sites within two otherwise hydrophobic pores. We suggest that an atomic level of detail is, in general, necessary for the reliable depiction of hydrophobicity for all protein surfaces. The present formulation can be implemented simply in a manner no more complex than current residue-based approaches. © 2013.

Integrating water exclusion theory into βcontacts to predict binding free energy changes and binding hot spots

PubMed Central

2014-01-01

Background Binding free energy and binding hot spots at protein-protein interfaces are two important research areas for understanding protein interactions. Computational methods have been developed previously for accurate prediction of binding free energy change upon mutation for interfacial residues. However, a large number of interrupted and unimportant atomic contacts are used in the training phase which caused accuracy loss. Results This work proposes a new method, βACV ASA , to predict the change of binding free energy after alanine mutations. βACV ASA integrates accessible surface area (ASA) and our newly defined β contacts together into an atomic contact vector (ACV). A β contact between two atoms is a direct contact without being interrupted by any other atom between them. A β contact’s potential contribution to protein binding is also supposed to be inversely proportional to its ASA to follow the water exclusion hypothesis of binding hot spots. Tested on a dataset of 396 alanine mutations, our method is found to be superior in classification performance to many other methods, including Robetta, FoldX, HotPOINT, an ACV method of β contacts without ASA integration, and ACV ASA methods (similar to βACV ASA but based on distance-cutoff contacts). Based on our data analysis and results, we can draw conclusions that: (i) our method is powerful in the prediction of binding free energy change after alanine mutation; (ii) β contacts are better than distance-cutoff contacts for modeling the well-organized protein-binding interfaces; (iii) β contacts usually are only a small fraction number of the distance-based contacts; and (iv) water exclusion is a necessary condition for a residue to become a binding hot spot. Conclusions βACV ASA is designed using the advantages of both β contacts and water exclusion. It is an excellent tool to predict binding free energy changes and binding hot spots after alanine mutation. PMID:24568581

Structural insights into the interaction of a monoclonal antibody and Nodal peptides by STD-NMR spectroscopy.

PubMed

Calvanese, Luisa; Focà, Annalia; Sandomenico, Annamaria; Focà, Giuseppina; Caporale, Andrea; Doti, Nunzianna; Iaccarino, Emanuela; Leonardi, Antonio; D'Auria, Gabriella; Ruvo, Menotti; Falcigno, Lucia

2017-12-15

Nodal is a growth factor expressed during early embryonic development, but reactivated in several advanced-stage cancers. Targeting of Nodal signaling, which occurs via the binding to Cripto-1 co-receptor, results in inhibition of cell aggressiveness and reduced tumor growth. The Nodal binding region to Cripto-1 was identified and targeted with a high affinity monoclonal antibody (3D1). By STD-NMR technique, we investigated the interaction of Nodal fragments with 3D1 with the aim to elucidate at atomic level the interaction surface. Data indicate with high accuracy the antibody-antigen contact atoms and confirm the information previously obtained by immune-enzymatic methods. Main residues contacted by 3D1 are P46, V47, E49 and E50, which belong to the Nodal loop involved in the interaction with the co-receptor. Copyright © 2017 Elsevier Ltd. All rights reserved.

Affinity comparison of different THCA synthase to CBGA using modeling computational approaches.

PubMed

Alaoui, Moulay Abdelaziz El; Ibrahimi, Azeddine; Semlali, Oussama; Tarhda, Zineb; Marouane, Melloul; Najwa, Alaoui; Soulaymani, Abdelmajid; Fahime, Elmostafa El

2014-01-01

The Δ(9-)Tetrahydrocannabinol (THCA) is the primary psychoactive compound of Cannabis Sativa. It is produced by Δ(1-) Tetrahydrocannabinolic acid synthase (THCA) which catalyzes the oxidative cyclization of cannabigerolic acid (CBGA) the precursor of the THCA. In this study, we were interested by the three dimensional structure of THCA synthase protein. Generation of models were done by MODELLER v9.11 and homology modeling with Δ1-tetrahydrocannabinolic acid (THCA) synthase X ray structure (PDB code 3VTE) on the basis of sequences retrieved from GenBank. Procheck, Errat, and Verify 3D tools were used to verify the reliability of the six 3D models obtained, the overall quality factor and the Prosa Z-score were also used to check the quality of the six modeled proteins. The RMSDs for C-alpha atoms, main-chain atoms, side-chain atoms and all atoms between the modeled structures and the corresponding template ranged between 0.290 Å-1.252 Å, reflecting the good quality of the obtained models. Our study of the CBGA-THCA synthase docking demonstrated that the active site pocket was successfully recognized using computational approach. The interaction energy of CBGA computed in 'fiber types' proteins ranged between -4.1 95 kcal/mol and -5.95 kcal/mol whereas in the 'drug type' was about -7.02 kcal/mol to -7.16 kcal/mol, which maybe indicate the important role played by the interaction energy of CBGA in the determination of the THCA level in Cannabis Sativa L. varieties. Finally, we have proposed an experimental design in order to explore the binding energy source of ligand-enzyme in Cannabis Sativa and the production level of the THCA in the absence of any information regarding the correlation between the enzyme affinity and THCA level production. This report opens the doors to more studies predicting the binding site pocket with accuracy from the perspective of the protein affinity and THCA level produced in Cannabis Sativa.

Site Identification by Ligand Competitive Saturation (SILCS) Simulations for Fragment-Based Drug Design

PubMed Central

Faller, Christina E.; Raman, E. Prabhu; MacKerell, Alexander D.; Guvench, Olgun

2015-01-01

Fragment-based drug design (FBDD) involves screening low molecular weight molecules (“fragments”) that correspond to functional groups found in larger drug-like molecules to determine their binding to target proteins or nucleic acids. Based on the principle of thermodynamic additivity, two fragments that bind non-overlapping nearby sites on the target can be combined to yield a new molecule whose binding free energy is the sum of those of the fragments. Experimental FBDD approaches, like NMR and X-ray crystallography, have proven very useful but can be expensive in terms of time, materials, and labor. Accordingly, a variety of computational FBDD approaches have been developed that provide different levels of detail and accuracy. The Site Identification by Ligand Competitive Saturation (SILCS) method of computational FBDD uses all-atom explicit-solvent molecular dynamics (MD) simulations to identify fragment binding. The target is “soaked” in an aqueous solution with multiple fragments having different identities. The resulting computational competition assay reveals what small molecule types are most likely to bind which regions of the target. From SILCS simulations, 3D probability maps of fragment binding called “FragMaps” can be produced. Based on the probabilities relative to bulk, SILCS FragMaps can be used to determine “Grid Free Energies (GFEs),” which provide per-atom contributions to fragment binding affinities. For essentially no additional computational overhead relative to the production of the FragMaps, GFEs can be used to compute Ligand Grid Free Energies (LGFEs) for arbitrarily complex molecules, and these LGFEs can be used to rank-order the molecules in accordance with binding affinities. PMID:25709034

Is the isolated ligand binding domain a good model of the domain in the native receptor?

PubMed

Deming, Dustin; Cheng, Qing; Jayaraman, Vasanthi

2003-05-16

Numerous studies have used the atomic level structure of the isolated ligand binding domain of the glutamate receptor to elucidate the agonist-induced activation and desensitization processes in this group of proteins. However, no study has demonstrated the structural equivalence of the isolated ligand binding fragments and the protein in the native receptor. In this report, using visible absorption spectroscopy we show that the electronic environment of the antagonist 6-cyano-7-nitro-2,3-dihydroxyquinoxaline is identical for the isolated protein and the native glutamate receptors expressed in cells. Our results hence establish that the local structure of the ligand binding site is the same in the two proteins and validate the detailed structure-function relationships that have been developed based on a comparison of the structure of the isolated ligand binding domain and electrophysiological consequences in the native receptor.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Chunhua; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 45108; Lv, Dashuai

Riboswitches are noncoding mRNA segments that can regulate the gene expression via altering their structures in response to specific metabolite binding. We proposed a coarse-grained Gaussian network model (GNM) to examine the unfolding and folding dynamics of adenosine deaminase (add) A-riboswitch upon the adenine dissociation, in which the RNA is modeled by a nucleotide chain with interaction networks formed by connecting adjoining atomic contacts. It was shown that the adenine binding is critical to the folding of the add A-riboswitch while the removal of the ligand can result in drastic increase of the thermodynamic fluctuations especially in the junction regionsmore » between helix domains. Under the assumption that the native contacts with the highest thermodynamic fluctuations break first, the iterative GNM simulations showed that the unfolding process of the adenine-free add A-riboswitch starts with the denature of the terminal helix stem, followed by the loops and junctions involving ligand binding pocket, and then the central helix domains. Despite the simplified coarse-grained modeling, the unfolding dynamics and pathways are shown in close agreement with the results from atomic-level MD simulations and the NMR and single-molecule force spectroscopy experiments. Overall, the study demonstrates a new avenue to investigate the binding and folding dynamics of add A-riboswitch molecule which can be readily extended for other RNA molecules.« less

Universal aspects of adhesion and atomic force microscopy

NASA Technical Reports Server (NTRS)

Banerjea, Amitava; Smith, John R.; Ferrante, John

1990-01-01

Adhesive energies are computed for flat and atomically sharp tips as a function of the normal distance to the substrate. The dependence of binding energies on tip shape is investigated. The magnitudes of the binding energies for the atomic force microscope are found to depend sensitively on tip material, tip shape and the sample site being probed. The form of the energy-distance curve, however, is universal and independent of these variables, including tip shape.

Enhanced Electromagnetic and Chemical/Biological Sensing. Properties of Atomic Cluster-Derived Materials

DTIC Science & Technology

2003-02-24

electron injection at interfaces, analysis of the voltage dependence of the electrostatic potential across molecules, the nature of binding at the...nanoscale titania into a metallic surface), analysis of the so-called band lineup between the molecular levels and the Fermi levels of the metal...observe the CNT’s in the electron microscope with the possibility to manipulate them externally and to apply potentials to them. These new

First stages of oxide growth on Al(1 1 0) and core-level shifts from density functional theory calculations

NASA Astrophysics Data System (ADS)

Lousada, Cláudio M.; Korzhavyi, Pavel A.

2018-05-01

The formation of islands of O-atoms is the dominant mode of growth of the oxide in the first stages of oxidation of Al(1 1 1). It is however unknown if a similar mechanism exists for other low index surfaces of Al. We performed a density functional theory (DFT) and ab initio molecular dynamics investigation of the first stages of the oxidation of Al(1 1 0) using two distinct models: a homogeneous surface disposition of O-atoms; and a model where the O-atoms are close-spaced forming clusters or islands. We investigated the surface reactions with oxygen up to a coverage of 2 ML and found that for both models the adsorption energy per dissociating O2(g) becomes more negative with increasing coverage. Our results show that for coverages up to 1.25 ML the oxide forms clusters or islands while for coverages higher than 1.5 ML the oxide covers the surface homogeneously. This is because the O-atoms bind preferably to neighboring sites even at the minimum coverage. With increasing coverage, the clusters of O start to form stripes along the [1 1 bar 0] direction. The work function (ϕ) of the surface decreases when going from bare Al(1 1 0) to up to 1 ML coverage of O-atoms, but for coverages of 1.25 ML and higher, ϕ increases. The Al 2p surface core level shifts (SCLS) shift towards higher binding energies with increasing surface coverage of O-atoms and start to approach the values of Al 2p in Al2O3 already at a coverage of 2ML. A relation between the SCLS and the coordination number of Al to O-atoms was made. The Al 2p SCLS increases with increasing coordination to O-atoms, for single, twofold and three-fourfold coordinated cations. For the O-atoms that terminate the surface at the short-bridge sites, the SCLS of O 1s, is largely affected by the proximity to other O-atoms. These results demonstrate that the cooperative effects between surface bound O-atoms have important roles in the mechanism of growth of the oxide at Al(1 1 0), and similarly to what happens for Al(1 1 1), the initial oxidation of Al(1 1 0) proceeds via the formation of islands of O-atoms.

Spin polarized first principles study of Mn doped gallium nitride monolayer nanosheet

NASA Astrophysics Data System (ADS)

Sharma, Venus; Kaur, Sumandeep; Srivastava, Sunita; Kumar, Tankeshwar

2017-05-01

The structural, electronic and magnetic properties of gallium nitride nanosheet (GaNs) doped with Mn atoms have been studied using spin polarized density functional theory. The binding energy per atom, Energy Band gap, Fermi energy, magnetic moment, electric dipole moment have been found. The doped nanosheet is found to be more stable than pure GaN monolayer nanosheet. Adsorption of Mn atom has been done at four different sites on GaNs which affects the fermi level position. It is found that depending on the doping site, Mn can behave both like p-type semiconductor and also as n-type semiconductor. Also, it is ascertained that Mn doped GaNs (GaNs-Mn) exhibits ferromagnetic behavior.

Theoretical analysis of the electronic properties of the sex pheromone and its analogue derivatives in the female processionary moth Thaumetopoea pytiocampa.

PubMed

Chamorro, Ester R; Sequeira, Alfredo F; Zalazar, M Fernanda; Peruchena, Nélida M

2008-09-15

In the present work, the distribution of the electronic charge density of the natural sex pheromone, the (Z)-13-hexadecen-11-ynyl acetate, in the female processionary moth, Thaumetopoea pytiocampa, and its nine analogue derivatives was studied within the framework of the Density Functional Theory and the Atoms in Molecules (AIM) Theory at B3LYP/6-31G *//B3LYP/6-31++G * * level. Additionally, molecular electrostatic potential (MEP) maps of the previously mentioned compounds were computed and compared. Furthermore, the substitution of hydrogen atoms from the methyl group in the acetate group by electron withdrawing substituents (i.e., halogen atoms) as well as the replacement effect of hydrogen by electron donor substituents (+I effect) as methyl group, were explored. The key feature of the topological distribution of the charge density in analogue compounds, such as the variations of the topological properties encountered in the region formed by neighbouring atoms from the substitution site were presented and discussed. Using topological parameters, such as electronic charge density, Laplacian, kinetic energy density, and potential energy density evaluated at bond critical points (BCP), we provide here a detailed analysis of the nature of the chemical bonding of these molecules. In addition, the atomic properties (population, charge, energy, volume, and dipole moment) were determined on selected atoms. These properties were analyzed at the substitution site (with respect to the natural sex pheromone) and related to the biological activity and to the possible binding site with the pheromone binding protein, (PBP). Moreover, the Laplacian function of the electronic density was used to locate electrophilic regions susceptible to be attacked (by deficient electron atoms or donor hydrogen). Our results indicate that the change in the atomic properties, such as electronic population and atomic volume, are sensitive indicators of the loss of the biological activity in the analogues studied here. The crucial interaction between the acetate group of the natural sex pheromone and the PBP is most likely to be a hydrogen bonding and the substitution of hydrogen atoms by electronegative atoms in the pheromone molecule reduces the hydrogen acceptor capacity. This situation is mirrored by the diminish of the electronic population on carbon and oxygen atoms at the carbonylic group in the halo-acetate group. Additionally, the modified acetate group (with electronegative atoms) shows new charge concentration critical points or regions of concentration of charge density in which an electrophilic attack can also occur. Finally, the use of the topological analysis based in the charge density distribution and its Laplacian function, in conjunction with MEP maps provides valuable information about the steric volume and electronic requirement of the sex pheromone for binding to the PBP.

Introducing various ligands into superhalogen anions reduces their electronic stabilities

NASA Astrophysics Data System (ADS)

Smuczyńska, Sylwia; Skurski, Piotr

2008-02-01

The vertical electron detachment energies (VDE) of six NaX2- anions (where X = F, Cl, Br) were calculated at the OVGF level with the 6-311++G(3df) basis sets. In all the cases studied the VDE exceeds the electron affinity of chlorine atom and thus those species were classified as superhalogen anions. The largest vertical binding energy was found for the NaF2- system (6.644 eV). The strong VDE dependence on the ligand type, ligand-central atom distance, and the character of the highest occupied molecular orbital (HOMO) was observed and discussed.

Room-temperature X-ray diffraction studies of cisplatin and carboplatin binding to His15 of HEWL after prolonged chemical exposure.

PubMed

Tanley, Simon W M; Schreurs, Antoine M M; Kroon-Batenburg, Loes M J; Helliwell, John R

2012-11-01

The anticancer complexes cisplatin and carboplatin are known to bind to both the Nδ and the Nℇ atoms of His15 of hen egg-white lysozyme (HEWL) in the presence of dimethyl sulfoxide (DMSO). However, neither binds in aqueous media after 4 d of crystallization and crystal growth, suggesting that DMSO facilitates cisplatin/carboplatin binding to the N atoms of His15 by an unknown mechanism. Crystals of HEWL cocrystallized with cisplatin in both aqueous and DMSO media, of HEWL cocrystallized with carboplatin in DMSO medium and of HEWL cocrystallized with cisplatin and N-acetylglucosamine (NAG) in DMSO medium were stored for between seven and 15 months. X-ray diffraction studies of these crystals were carried out on a Bruker APEX II home-source diffractometer at room temperature. Room-temperature X-ray diffraction data collection removed the need for cryoprotectants to be used, ruling out any effect that the cryoprotectants might have had on binding to the protein. Both cisplatin and carboplatin still bind to both the Nδ and Nℇ atoms of His15 in DMSO media as expected, but more detail for the cyclobutanedicarboxylate (CBDC) moiety of carboplatin was observed at the Nℇ binding site. However, two molecules of cisplatin were now observed to be bound to His15 in aqueous conditions. The platinum peak positions were identified using anomalous difference electron-density maps as a cross-check with Fo-Fc OMIT electron-density maps. The occupancies of each binding site were calculated using SHELXTL. These results show that over time cisplatin binds to both N atoms of His15 of HEWL in aqueous media, whereas this binding is speeded up in the presence of DMSO. The implication of cisplatin binding to proteins after a prolonged period of time is an important consideration for the length of treatment in patients who are given cisplatin.

Interfacial phenomena in high-kappa dielectrics

NASA Astrophysics Data System (ADS)

Mathew, Anoop

The introduction of novel high-kappa dielectric materials to replace the traditional SiO2 insulating layer in CMOS transistors is a watershed event in the history of transistor development. Further, replacement of the traditional highly-doped polycrystalline silicon gate electrode with a new set of materials for metal gates complicates the transition and introduces further integration challenges. A whole variety of new material surfaces and interfaces are thus introduced that merit close investigation to determine parameters for optimal device performance. Nitrogen is a key component that improves the performance of a variety of materials for the next generation of these CMOS transistors. Nitrogen is introduced into new gate dielectric materials such as hafnium silicates as well as in potential metal gate materials such as hafnium nitride. A photoemission study of the binding energies of the various atoms in these systems using photoemission reveals the nature of the atomic bonding. The current study compares hafnium silicates of various compositions which were thermally nitrided at different temperatures in ammonia, hafnium nitrides, and thin HfO2 films using photoelectron spectroscopy. A recurring theme that is explored is the competition between oxygen and nitrogen atoms in bonding with hafnium and other atoms. The N 1s photoemission peak is seen to have contributions from its bonding with hafnium, oxygen, and silicon atoms. The Hf 4f and O 1s spectra similarly exhibit signatures of their bonding environment with their neighboring atoms. Angle resolved photoemission and in-situ annealing/argon sputtering experiments are used to elucidate the nature of the bonding and its evolution with processing. A nondestructive profilitng of nitrogen distribution as a function of composition in nitrided hafnium silicates is also constructed using angle resolved photoemission as a function of the take-off angle. These results are corroborated with depth reconstruction obtained using medium energy ion scattering (MEIS). A comparison of samples nitrided at progressively increasing temperatures in an ammonia environment shows substitution of oxygen with nitrogen atoms and increasing penetration of nitrogen into the gate stack. Trends in the binding energy of the the as-prepared hafnium silicates suggest that they are non-phase separated, and the binding energy of the hafnium and silicon track the relative composition. Upon being subject to rapid thermal annealing, the samples are observed to show behavior consistent with phase separation. There is also the evidence of charges at the oxide/Si interface that modify the expected behavior of the shifts in binding energy. In another set of experiments, a one-cycle atomic layer deposition (ALD) growth reaction on the water terminated Si(100) -- (2x1) surface is shown to lead to successful nucleation, high metal oxide coverage, and an abrupt metal-oxide/silicon interface as confirmed by photoemission, reflection high energy electron diffraction (RHEED), and Rutherford back scattering (RBS) measurements. Photoemission results confirm the coordination states of the hafnium and oxygen atoms. A Hf 4f core level shift is observed and assigned to the presence of the Si-O-Hf bonding environment with the more electronegative Si atom inducing the binding energy shift. This Hf 4f shift is smaller than that reported previously for silicates because of the difference of the semiconductor bonding environment. The subspecies *(O)2HfCl2 and *OHfCl3 are seen to be the predominant intermediate species in these reactions and photoemission results provide corroborative evidence for their presence. Experiments indicate that the hydroxyl sites bound to Si(100) are active for adsorption. The abrupt interface could be useful for aggressive Effective Oxide Thickness (EOT) scaling.

Predicting the Effect of Mutations on Protein-Protein Binding Interactions through Structure-Based Interface Profiles

PubMed Central

Brender, Jeffrey R.; Zhang, Yang

2015-01-01

The formation of protein-protein complexes is essential for proteins to perform their physiological functions in the cell. Mutations that prevent the proper formation of the correct complexes can have serious consequences for the associated cellular processes. Since experimental determination of protein-protein binding affinity remains difficult when performed on a large scale, computational methods for predicting the consequences of mutations on binding affinity are highly desirable. We show that a scoring function based on interface structure profiles collected from analogous protein-protein interactions in the PDB is a powerful predictor of protein binding affinity changes upon mutation. As a standalone feature, the differences between the interface profile score of the mutant and wild-type proteins has an accuracy equivalent to the best all-atom potentials, despite being two orders of magnitude faster once the profile has been constructed. Due to its unique sensitivity in collecting the evolutionary profiles of analogous binding interactions and the high speed of calculation, the interface profile score has additional advantages as a complementary feature to combine with physics-based potentials for improving the accuracy of composite scoring approaches. By incorporating the sequence-derived and residue-level coarse-grained potentials with the interface structure profile score, a composite model was constructed through the random forest training, which generates a Pearson correlation coefficient >0.8 between the predicted and observed binding free-energy changes upon mutation. This accuracy is comparable to, or outperforms in most cases, the current best methods, but does not require high-resolution full-atomic models of the mutant structures. The binding interface profiling approach should find useful application in human-disease mutation recognition and protein interface design studies. PMID:26506533

Where's water? The many binding sites of hydantoin.

PubMed

Gruet, Sébastien; Pérez, Cristóbal; Steber, Amanda L; Schnell, Melanie

2018-02-21

Prebiotic hydantoin and its complexes with one and two water molecules are investigated using high-resolution broadband rotational spectroscopy in the 2-8 GHz frequency range. The hyperfine structure due to the nuclear quadrupole coupling of the two 14 N atoms is analysed for the monomer and the complexes. This characteristic hyperfine structure will support a definitive assignment from low frequency radioastronomy data. Experiments with H 2 18 O provide accurate experimental information on the preferred binding sites of water, which are compared with quantum-chemically calculated coordinates. In the 2-water complexes, the water molecules bind to hydantoin as a dimer instead of individually, indicating the strong water-water interactions. This information provides first insight on how hydantoin interacts with water on the molecular level.

Exploration of gated ligand binding recognizes an allosteric site for blocking FABP4-protein interaction.

PubMed

Li, Yan; Li, Xiang; Dong, Zigang

2015-12-28

Fatty acid binding protein 4 (FABP4), reversibly binding to fatty acids and other lipids with high affinities, is a potential target for treatment of cancers. The binding site of FABP4 is buried in an interior cavity and thereby ligand binding/unbinding is coupled with opening/closing of FABP4. It is a difficult task both experimentally and computationally to illuminate the entry or exit pathway, especially with the conformational gating. In this report we combine extensive computer simulations, clustering analysis, and the Markov state model to investigate the binding mechanism of FABP4 and troglitazone. Our simulations capture spontaneous binding and unbinding events as well as the conformational transition of FABP4 between the open and closed states. An allosteric binding site on the protein surface is recognized for the development of novel FABP4 inhibitors. The binding affinity is calculated and compared with the experimental value. The kinetic analysis suggests that ligand residence on the protein surface may delay the binding process. Overall, our results provide a comprehensive picture of ligand diffusion on the protein surface, ligand migration into the buried cavity, and the conformational change of FABP4 at an atomic level.

Binding of dinitrogen to an iron-sulfur-carbon site

NASA Astrophysics Data System (ADS)

Čorić, Ilija; Mercado, Brandon Q.; Bill, Eckhard; Vinyard, David J.; Holland, Patrick L.

2015-10-01

Nitrogenases are the enzymes by which certain microorganisms convert atmospheric dinitrogen (N2) to ammonia, thereby providing essential nitrogen atoms for higher organisms. The most common nitrogenases reduce atmospheric N2 at the FeMo cofactor, a sulfur-rich iron-molybdenum cluster (FeMoco). The central iron sites that are coordinated to sulfur and carbon atoms in FeMoco have been proposed to be the substrate binding sites, on the basis of kinetic and spectroscopic studies. In the resting state, the central iron sites each have bonds to three sulfur atoms and one carbon atom. Addition of electrons to the resting state causes the FeMoco to react with N2, but the geometry and bonding environment of N2-bound species remain unknown. Here we describe a synthetic complex with a sulfur-rich coordination sphere that, upon reduction, breaks an Fe-S bond and binds N2. The product is the first synthetic Fe-N2 complex in which iron has bonds to sulfur and carbon atoms, providing a model for N2 coordination in the FeMoco. Our results demonstrate that breaking an Fe-S bond is a chemically reasonable route to N2 binding in the FeMoco, and show structural and spectroscopic details for weakened N2 on a sulfur-rich iron site.

Phosphonic Acids on an Atomically Defined Oxide Surface: The Binding Motif Changes with Surface Coverage.

PubMed

Schuschke, Christian; Schwarz, Matthias; Hohner, Chantal; Silva, Thais N; Fromm, Lukas; Döpper, Tibor; Görling, Andreas; Libuda, Jörg

2018-04-19

We have studied the anchoring mechanism of a phosphonic acid on an atomically defined oxide surface. Using time-resolved infrared reflection absorption spectroscopy, we investigated the reaction of deuterated phenylphosphonic acid (DPPA, C 6 H 5 PO 3 D 2 ) with an atomically defined Co 3 O 4 (111) surface in situ during film growth by physical vapor deposition. We show that the binding motif of the phosphonate anchor group changes as a function of coverage. At low coverage, DPPA binds in the form of a chelating tridentate phosphonate, while a transition to a chelating bidentate occurs close to monolayer saturation coverage. However, the coverage-dependent change in the binding motif is not associated with a major change of the molecular orientation, suggesting that the rigid phosphonate linker always maintains the DPPA in a strongly tilted orientation irrespective of the surface coverage.

A hierarchical coarse-grained (all-atom to all residue) approach to peptides (P1, P2) binding with a graphene sheet

NASA Astrophysics Data System (ADS)

Pandey, Ras; Kuang, Zhifeng; Farmer, Barry; Kim, Sang; Naik, Rajesh

2012-02-01

Recently, Kim et al. [1] have found that peptides P1: HSSYWYAFNNKT and P2: EPLQLKM bind selectively to graphene surfaces and edges respectively which are critical in modulating both the mechanical as well as electronic transport properties of graphene. Such distinctions in binding sites (edge versus surface) observed in electron micrographs were verified by computer simulation by an all-atomic model that captures the pi-pi bonding. We propose a hierarchical approach that involves input from the all-atom Molecular Dynamics (MD) study (with atomistic detail) into a coarse-grained Monte Carlo simulation to extend this study further to a larger scale. The binding energy of a free amino acid with the graphene sheet from all-atom simulation is used in the interaction parameter for the coarse-grained approach. Peptide chain executes its stochastic motion with the Metropolis algorithm. We investigate a number of local and global physical quantities and find that peptide P1 is likely to bind more strongly to graphene sheet than P2 and that it is anchored by three residues ^4Y^5W^6Y. [1] S.N. Kim et al J. Am. Chem. Soc. 133, 14480 (2011).

Plasmon excitations in doped square-lattice atomic clusters

NASA Astrophysics Data System (ADS)

Wang, Yaxin; Yu, Ya-Bin

2017-12-01

Employing the tight-binding model, we theoretically study the properties of the plasmon excitations in doped square-lattice atomic clusters. The results show that the dopant atoms would blur the absorption spectra, and give rise to extra plasmon resonant peaks as reported in the literature; however, our calculated external-field induced oscillating charge density shows that no obvious evidences indicate the so-called local mode of plasmon appearing in two-dimensional-doped atomic clusters, but the dopants may change the symmetry of the charge distribution. Furthermore, we show that the disorder of the energy level due to dopant makes the absorption spectrum has a red- or blue-shift, which depends on the position of impurities; disorder of hopping due to dopant makes a blue- or red-shift, a larger (smaller) hopping gives a blue-shift (red-shift); and a larger (smaller) host-dopant and dopant-dopant intersite coulomb repulsion induces a blue-shift (red-shift).

Quantized evaporation from liquid helium

NASA Astrophysics Data System (ADS)

Baird, M. J.; Hope, F. R.; Wyatt, A. F. G.

1983-07-01

The atomic-level kinetics of evaporation from a liquid surface are investigated experimentally for the case of liquid He-4. A pulse of phonons was injected by a submerged thin-film heater into purified He-4 (cooled to less than about 0.1 K) and collimated into a beam directed at the liquid surface; the atoms liberated at the surface were detected by a bolometer. The energy of the incident phonon and the kinetic energy of the liberated atom were calculated by determining the group velocity (from the minimum time elapsed between the beginning of the heater pulse and the arrival of the leading edge of the signal) and combining it with neutron-measured excitation dispersion data. Measurements were also made with a mixture of He-3 and He-4. The results are shown to be in good agreement with theoretical predictions of the phonon-induced quantum evaporation of surface atoms: the energy of the phonon is divided between the kinetic energy of the liberated atom and the energy required to overcome the binding forces.

The magic triangle goes MAD: experimental phasing with a bromine derivative

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beck, Tobias, E-mail: tbeck@shelx.uni-ac.gwdg.de; Gruene, Tim; Sheldrick, George M.

2010-04-01

5-Amino-2, 4, 6-tribromoisophthalic acid is used as a phasing tool for protein structure determination by MAD phasing. It is the second representative of a novel class of compounds for heavy-atom derivatization that combine heavy atoms with amino and carboxyl groups for binding to proteins. Experimental phasing is an essential technique for the solution of macromolecular structures. Since many heavy-atom ion soaks suffer from nonspecific binding, a novel class of compounds has been developed that combines heavy atoms with functional groups for binding to proteins. The phasing tool 5-amino-2, 4, 6-tribromoisophthalic acid (B3C) contains three functional groups (two carboxylate groups andmore » one amino group) that interact with proteins via hydrogen bonds. Three Br atoms suitable for anomalous dispersion phasing are arranged in an equilateral triangle and are thus readily identified in the heavy-atom substructure. B3C was incorporated into proteinase K and a multiwavelength anomalous dispersion (MAD) experiment at the Br K edge was successfully carried out. Radiation damage to the bromine–carbon bond was investigated. A comparison with the phasing tool I3C that contains three I atoms for single-wavelength anomalous dispersion (SAD) phasing was also carried out.« less

Design of stapled DNA-minor-groove-binding molecules with a mutable atom simulated annealing method

NASA Astrophysics Data System (ADS)

Walker, Wynn L.; Kopka, Mary L.; Dickerson, Richard E.; Goodsell, David S.

1997-11-01

We report the design of optimal linker geometries for the synthesis of stapledDNA-minor-groove-binding molecules. Netropsin, distamycin, and lexitropsinsbind side-by-side to mixed-sequence DNA and offer an opportunity for thedesign of sequence-reading molecules. Stapled molecules, with two moleculescovalently linked side-by-side, provide entropic gains and restrain theposition of one molecule relative to its neighbor. Using a free-atom simulatedannealing technique combined with a discrete mutable atom definition, optimallengths and atomic composition for covalent linkages are determined, and anovel hydrogen bond `zipper' is proposed to phase two molecules accuratelyside-by-side.

Tight-binding calculation studies of vacancy and adatom defects in graphene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Wei; Lu, Wen-Cai; Zhang, Hong-Xing

2016-02-19

Computational studies of complex defects in graphene usually need to deal with a larger number of atoms than the current first-principles methods can handle. We show a recently developed three-center tight-binding potential for carbon is very efficient for large scale atomistic simulations and can accurately describe the structures and energies of various defects in graphene. Using the three-center tight-binding potential, we have systematically studied the stable structures and formation energies of vacancy and embedded-atom defects of various sizes up to 4 vacancies and 4 embedded atoms in graphene. In conclusion, our calculations reveal low-energy defect structures and provide a moremore » comprehensive understanding of the structures and stability of defects in graphene.« less

The Nature of the Interactions in Triethanolammonium-Based Ionic Liquids. A Quantum Chemical Study.

PubMed

Fedorova, Irina V; Safonova, Lyubov P

2018-05-10

Structural features and interionic interactions play a crucial role in determining the overall stability of ionic liquids and their physicochemical properties. Therefore, we performed high-level quantum-chemical study of different cation-anion pairs representing the building units of protic ionic liquids based on triethanolammonium cation and anions of sulfuric, nitric, phosphoric, and phosphorus acids to provide essential insight into these phenomena at the molecular level. It was shown that every structure is stabilized through multiple H bonds between the protons in the N-H and O-H groups of the cation and different oxygen atoms of the anion acid. Using atoms in molecules topological parameters and natural bond orbital analysis, we determined the nature and strength of these interactions. Our calculations suggest that the N-H group of the cation has more proton donor-like character than the O-H group that makes the N-H···O hydrogen bonds stronger. A close relation between the binding energies of these ion pairs and experimental melting points was established: the smaller the absolute value of the binding energy between ions, the lower is the melting point.

The role of amino acid electron-donor/acceptor atoms in host-cell binding peptides is associated with their 3D structure and HLA-binding capacity in sterile malarial immunity induction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Patarroyo, Manuel E., E-mail: mepatarr@mail.com; Universidad Nacional de Colombia, Bogota; Almonacid, Hannia

Highlights: Black-Right-Pointing-Pointer Fundamental residues located in some HABPs are associated with their 3D structure. Black-Right-Pointing-Pointer Electron-donor atoms present in {beta}-turn, random, distorted {alpha}-helix structures. Black-Right-Pointing-Pointer Electron-donor atoms bound to HLA-DR53. Black-Right-Pointing-Pointer Electron-acceptor atoms present in regular {alpha}-helix structure bound to HLA-DR52. -- Abstract: Plasmodium falciparum malaria continues being one of the parasitic diseases causing the highest worldwide mortality due to the parasite's multiple evasion mechanisms, such as immunological silence. Membrane and organelle proteins are used during invasion for interactions mediated by high binding ability peptides (HABPs); these have amino acids which establish hydrogen bonds between them in some of theirmore » critical binding residues. Immunisation assays in the Aotus model using HABPs whose critical residues had been modified have revealed a conformational change thereby enabling a protection-inducing response. This has improved fitting within HLA-DR{beta}1{sup Asterisk-Operator} molecules where amino acid electron-donor atoms present in {beta}-turn, random or distorted {alpha}-helix structures preferentially bound to HLA-DR53 molecules, whilst HABPs having amino acid electron-acceptor atoms present in regular {alpha}-helix structure bound to HLA-DR52. This data has great implications for vaccine development.« less

Arsenic Directly Binds to and Activates the Yeast AP-1-Like Transcription Factor Yap8

PubMed Central

Kumar, Nallani Vijay; Yang, Jianbo; Pillai, Jitesh K.; Rawat, Swati; Solano, Carlos; Kumar, Abhay; Grøtli, Morten; Stemmler, Timothy L.; Rosen, Barry P.

2015-01-01

The AP-1-like transcription factor Yap8 is critical for arsenic tolerance in the yeast Saccharomyces cerevisiae. However, the mechanism by which Yap8 senses the presence of arsenic and activates transcription of detoxification genes is unknown. Here we demonstrate that Yap8 directly binds to trivalent arsenite [As(III)] in vitro and in vivo and that approximately one As(III) molecule is bound per molecule of Yap8. As(III) is coordinated by three sulfur atoms in purified Yap8, and our genetic and biochemical data identify the cysteine residues that form the binding site as Cys132, Cys137, and Cys274. As(III) binding by Yap8 does not require an additional yeast protein, and Yap8 is regulated neither at the level of localization nor at the level of DNA binding. Instead, our data are consistent with a model in which a DNA-bound form of Yap8 acts directly as an As(III) sensor. Binding of As(III) to Yap8 triggers a conformational change that in turn brings about a transcriptional response. Thus, As(III) binding to Yap8 acts as a molecular switch that converts inactive Yap8 into an active transcriptional regulator. This is the first report to demonstrate how a eukaryotic protein couples arsenic sensing to transcriptional activation. PMID:26711267

Arsenic Directly Binds to and Activates the Yeast AP-1-Like Transcription Factor Yap8

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, Nallani Vijay; Yang, Jianbo; Pillai, Jitesh K.

The AP-1-like transcription factor Yap8 is critical for arsenic tolerance in the yeastSaccharomyces cerevisiae. However, the mechanism by which Yap8 senses the presence of arsenic and activates transcription of detoxification genes is unknown. Here we demonstrate that Yap8 directly binds to trivalent arsenite [As(III)]in vitroandin vivoand that approximately one As(III) molecule is bound per molecule of Yap8. As(III) is coordinated by three sulfur atoms in purified Yap8, and our genetic and biochemical data identify the cysteine residues that form the binding site as Cys132, Cys137, and Cys274. As(III) binding by Yap8 does not require an additional yeast protein, and Yap8more » is regulated neither at the level of localization nor at the level of DNA binding. Instead, our data are consistent with a model in which a DNA-bound form of Yap8 acts directly as an As(III) sensor. Binding of As(III) to Yap8 triggers a conformational change that in turn brings about a transcriptional response. Thus, As(III) binding to Yap8 acts as a molecular switch that converts inactive Yap8 into an active transcriptional regulator. This is the first report to demonstrate how a eukaryotic protein couples arsenic sensing to transcriptional activation.« less

Approach to the unfolding and folding dynamics of add A-riboswitch upon adenine dissociation using a coarse-grained elastic network model

NASA Astrophysics Data System (ADS)

Li, Chunhua; Lv, Dashuai; Zhang, Lei; Yang, Feng; Wang, Cunxin; Su, Jiguo; Zhang, Yang

2016-07-01

Riboswitches are noncoding mRNA segments that can regulate the gene expression via altering their structures in response to specific metabolite binding. We proposed a coarse-grained Gaussian network model (GNM) to examine the unfolding and folding dynamics of adenosine deaminase (add) A-riboswitch upon the adenine dissociation, in which the RNA is modeled by a nucleotide chain with interaction networks formed by connecting adjoining atomic contacts. It was shown that the adenine binding is critical to the folding of the add A-riboswitch while the removal of the ligand can result in drastic increase of the thermodynamic fluctuations especially in the junction regions between helix domains. Under the assumption that the native contacts with the highest thermodynamic fluctuations break first, the iterative GNM simulations showed that the unfolding process of the adenine-free add A-riboswitch starts with the denature of the terminal helix stem, followed by the loops and junctions involving ligand binding pocket, and then the central helix domains. Despite the simplified coarse-grained modeling, the unfolding dynamics and pathways are shown in close agreement with the results from atomic-level MD simulations and the NMR and single-molecule force spectroscopy experiments. Overall, the study demonstrates a new avenue to investigate the binding and folding dynamics of add A-riboswitch molecule which can be readily extended for other RNA molecules.

Multi-level molecular modelling for plasma medicine

NASA Astrophysics Data System (ADS)

Bogaerts, Annemie; Khosravian, Narjes; Van der Paal, Jonas; Verlackt, Christof C. W.; Yusupov, Maksudbek; Kamaraj, Balu; Neyts, Erik C.

2016-02-01

Modelling at the molecular or atomic scale can be very useful for obtaining a better insight in plasma medicine. This paper gives an overview of different atomic/molecular scale modelling approaches that can be used to study the direct interaction of plasma species with biomolecules or the consequences of these interactions for the biomolecules on a somewhat longer time-scale. These approaches include density functional theory (DFT), density functional based tight binding (DFTB), classical reactive and non-reactive molecular dynamics (MD) and united-atom or coarse-grained MD, as well as hybrid quantum mechanics/molecular mechanics (QM/MM) methods. Specific examples will be given for three important types of biomolecules, present in human cells, i.e. proteins, DNA and phospholipids found in the cell membrane. The results show that each of these modelling approaches has its specific strengths and limitations, and is particularly useful for certain applications. A multi-level approach is therefore most suitable for obtaining a global picture of the plasma-biomolecule interactions.

AutoSite: an automated approach for pseudo-ligands prediction—from ligand-binding sites identification to predicting key ligand atoms

PubMed Central

Ravindranath, Pradeep Anand; Sanner, Michel F.

2016-01-01

Motivation: The identification of ligand-binding sites from a protein structure facilitates computational drug design and optimization, and protein function assignment. We introduce AutoSite: an efficient software tool for identifying ligand-binding sites and predicting pseudo ligand corresponding to each binding site identified. Binding sites are reported as clusters of 3D points called fills in which every point is labelled as hydrophobic or as hydrogen bond donor or acceptor. From these fills AutoSite derives feature points: a set of putative positions of hydrophobic-, and hydrogen-bond forming ligand atoms. Results: We show that AutoSite identifies ligand-binding sites with higher accuracy than other leading methods, and produces fills that better matches the ligand shape and properties, than the fills obtained with a software program with similar capabilities, AutoLigand. In addition, we demonstrate that for the Astex Diverse Set, the feature points identify 79% of hydrophobic ligand atoms, and 81% and 62% of the hydrogen acceptor and donor hydrogen ligand atoms interacting with the receptor, and predict 81.2% of water molecules mediating interactions between ligand and receptor. Finally, we illustrate potential uses of the predicted feature points in the context of lead optimization in drug discovery projects. Availability and Implementation: http://adfr.scripps.edu/AutoDockFR/autosite.html Contact: sanner@scripps.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27354702

Impact of genetic variation on three dimensional structure and function of proteins

PubMed Central

Bhattacharya, Roshni; Rose, Peter W.; Burley, Stephen K.

2017-01-01

The Protein Data Bank (PDB; http://wwpdb.org) was established in 1971 as the first open access digital data resource in biology with seven protein structures as its initial holdings. The global PDB archive now contains more than 126,000 experimentally determined atomic level three-dimensional (3D) structures of biological macromolecules (proteins, DNA, RNA), all of which are freely accessible via the Internet. Knowledge of the 3D structure of the gene product can help in understanding its function and role in disease. Of particular interest in the PDB archive are proteins for which 3D structures of genetic variant proteins have been determined, thus revealing atomic-level structural differences caused by the variation at the DNA level. Herein, we present a systematic and qualitative analysis of such cases. We observe a wide range of structural and functional changes caused by single amino acid differences, including changes in enzyme activity, aggregation propensity, structural stability, binding, and dissociation, some in the context of large assemblies. Structural comparison of wild type and mutated proteins, when both are available, provide insights into atomic-level structural differences caused by the genetic variation. PMID:28296894

The influence of Cu+ binding to hypoxanthine on stabilization of mismatches involving hypoxanthine and DNA bases: A DFT study.

PubMed

Masoodi, Hamid Reza; Bagheri, Sotoodeh; Ghaderi, Zahra

2018-05-14

In the present work, the influence of Cu + binding to N3- and N7-positions of hypoxanthine on energetic, geometrical and topological properties of hypoxanthine-guanine, hypoxanthine-adenine, hypoxanthine-cytosine, hypoxanthine-thymine and hypoxanthine-hypoxanthine mismatches is theoretically investigated. The calculations, in gas phase, are performed at B3LYP/6-311++G(3df,3pd) level of theory. Unlike the other mispairs, Cu + binding to N3-position of hypoxanthine causes the proton transfer process from enol form of hypoxanthine to imino forms of adenine and cytosine. This process also occurs in all mismatches having enol form of hypoxanthine when Cu + binds to N7-position of hypoxanthine. The mismatches are stabilized by hydrogen bonds. The influence of Cu + on hydrogen bonds is also examined by atoms in molecules (AIM) and natural bond orbital (NBO) analyses.

Electronic and Structural Parameters of Phosphorus-Oxygen Bonds in Inorganic Phosphate Crystals

NASA Astrophysics Data System (ADS)

Atuchin, V. V.; Kesler, V. G.; Pervukhina, N. V.

Wide set of experimental results on binding energy of photoelectrons emitted from P 2p, P 2s, and O 1s core levels has been observed for inorganic phosphate crystals and the parameters were compared using energy differences Δ(O 1s - P 2p) and Δ (O 1s - P 2s) as most robust characteristics. Linear dependence of the binding energy difference on mean chemical bond length L(P-O) between phosphorus and oxygen atoms has been found. The functions are of the forms: Δ (O 1s - P 2p) (eV) = 375.54 + 0.146 · L(P-O) (pm) and Δ (O 1s - P 2s) (eV) = 320.77 + 0.129 · L(P-O) (pm). The dependencies are general for inorganic phosphates and may be used in quantitative component analysis of X-ray photoemission spectra of complex oxide compounds including functional groups with different coordination of P and O atoms.

Structural analysis of binding functionality of folic acid-PEG dendrimers against folate receptor.

PubMed

Sampogna-Mireles, Diana; Araya-Durán, Ingrid D; Márquez-Miranda, Valeria; Valencia-Gallegos, Jesús A; González-Nilo, Fernando D

2017-03-01

Dendrimers functionalized with folic acid (FA) are drug delivery systems that can selectively target cancer cells with folate receptors (FR-α) overexpression. Incorporation of polyethylene glycol (PEG) can enhance dendrimers solubility and pharmacokinetics, but ligand-receptor binding must not be affected. In this work we characterized, at atomic level, the binding functionality of conventional site-specific dendrimers conjugated with FA with PEG 750 or PEG 3350 as a linker. After Molecular Dynamics simulation, we observed that both PEG's did not interfere over ligand-receptor binding functionality. Although binding kinetics could be notably affected, the folate fragment from both dendrimers remained exposed to the solvent before approaching selectively to FR-α. PEG 3350 provided better solubility and protection from enzymatic degradation to the dendrimer than PEG 750. Also, FA-PEG3350 dendrimer showed a slightly better interaction with FR-α than FA-PEG750 dendrimer. Therefore, theoretical evidence supports that both dendrimers are suitable as drug delivery systems for cancer therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Magnetic field dependence of the atomic collapse state in graphene

NASA Astrophysics Data System (ADS)

Moldovan, D.; Ramezani Masir, M.; Peeters, F. M.

2018-01-01

Quantum electrodynamics predicts that heavy atoms (Z > Zc ≈ 170 ) will undergo the process of atomic collapse where electrons sink into the positron continuum and a new family of so-called collapsing states emerges. The relativistic electrons in graphene exhibit the same physics but at a much lower critical charge (Zc ≈ 1 ) which has made it possible to confirm this phenomenon experimentally. However, there exist conflicting predictions on the effect of a magnetic field on atomic collapse. These theoretical predictions are based on the continuum Dirac-Weyl equation, which does not have an exact analytical solution for the interplay of a supercritical Coulomb potential and the magnetic field. Approximative solutions have been proposed, but because the two effects compete on similar energy scales, the theoretical treatment varies depending on the regime which is being considered. These limitations are overcome here by starting from a tight-binding approach and computing exact numerical results. By avoiding special limit cases, we found a smooth evolution between the different regimes. We predict that the atomic collapse effect persists even after the magnetic field is activated and that the critical charge remains unchanged. We show that the atomic collapse regime is characterized: (1) by a series of Landau level anticrossings and (2) by the absence of \\sqrt{B} scaling of the Landau levels with regard to magnetic field strength.

Ultralong-range Rydberg Molecules: Investigation of a Novel Binding Mechanism

NASA Astrophysics Data System (ADS)

Butscher, Björn; Bendkowsky, Vera; Nipper, Johannes; Balewski, Jonathan; Shaffer, James P.; Löw, Robert; Pfau, Tilman

2010-03-01

For highly excited Rydberg atoms, the scattering of the Rydberg electron from a nearby polarizable ground state atom can generate an attractive mean-field potential which is able to bind the ground state atom to the Rydberg atom within the Rydberg electron wave function at binding energies ranging from a few MHz to hundreds of MHz[1]. We present spectroscopic data on the observation of various bound states including the vibrational ground and excited states of rubidium dimers Rb(5S)-Rb(nS) as well as those of trimer states. Furthermore, we show calculations that reproduce the observed binding energies remarkably well and reveal that some of the excited states are purely bound by quantum reflection at a shape resonance for p-wave scattering [2]. To further characterize the coherent excitation of the molecular states, we performed echo experiments. [0pt] [1] V. Bendkowsky, B. Butscher, J. Nipper, J. P. Shaffer, R. Löw, T. Pfau, Nature 458, 1005 (2009); [2] V. Bendkowsky, B. Butscher, J. Nipper, J. Balewski, J. P. Shaffer, R. Löw, T. Pfau, W. Li, J. Stanojevic, T. Pohl,and J. M. Rost, arXiv:0912.4058 (2009)

Composite Structural Motifs of Binding Sites for Delineating Biological Functions of Proteins

PubMed Central

Kinjo, Akira R.; Nakamura, Haruki

2012-01-01

Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs that represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures. PMID:22347478

Is Einstein the Father of the Atomic Bomb

NASA Astrophysics Data System (ADS)

Lustig, Harry

2009-05-01

Soon after the American atomic bombs were dropped on Hiroshima and Nagasaki, the notion took hold in the popular mind that Albert Einstein was ``the father of the bomb.'' The claim of paternity rests on the belief that E=mc2 is what makes the release of enormous amounts of energy in the fission process possible and that the atomic bomb could not have been built without it. This is a misapprehension. Most physicists have known that all along. Nevertheless in his reaction to the opera Dr. Atomic, a prominent physicist claimed that Einstein's discovery that matter can be transformed into energy ``is precisely what made the bomb possible.'' In fact what makes the fission reaction and one of its applications,the atomic bomb, possible is the smaller binding energies of fission products compared to the binding energies of the nuclei that undergo fission.The binding energies of nuclei are a well understood consequence of the numbers and arrangements of protons and neutrons in the nucleus and of quantum-mechanical effects. The realization that composite systems have binding energies predates relativity. In the 19th century they were ascribed to potential and other forms of energy that reside in the system. With Einstein they became rest mass energy. While E=mc2 is not the cause of fission, measuring the masses of the participants in the reaction does permit an easy calculation of the kinetic energy that is released.

Molecular mechanism of membrane binding of the GRP1 PH domain.

PubMed

Lai, Chun-Liang; Srivastava, Anand; Pilling, Carissa; Chase, Anna R; Falke, Joseph J; Voth, Gregory A

2013-09-09

The pleckstrin homology (PH) domain of the general receptor of phosphoinositides 1 (GRP1) protein selectively binds to a rare signaling phospholipid, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), in the membrane. The specific PIP3 lipid docking of GRP1 PH domain is essential to protein cellular function and is believed to occur in a stepwise process, electrostatic-driven membrane association followed by the specific PIP3 binding. By a combination of all-atom molecular dynamics (MD) simulations, coarse-grained analysis, electron paramagnetic resonance (EPR) membrane docking geometry, and fluorescence resonance energy transfer (FRET) kinetic studies, we have investigated the search and bind process in the GRP1 PH domain at the molecular scale. We simulated the two membrane binding states of the GRP1 PH domain in the PIP3 search process, before and after the GRP1 PH domain docks with the PIP3 lipid. Our results suggest that the background anionic phosphatidylserine lipids, which constitute around one-fifth of the membrane by composition, play a critical role in the initial stages of recruiting protein to the membrane surface through non-specific electrostatic interactions. Our data also reveal a previously unseen transient membrane association mechanism that is proposed to enable a two-dimensional "hopping" search of the membrane surface for the rare PIP3 target lipid. We further modeled the PIP3-bound membrane-protein system using the EPR membrane docking structure for the MD simulations, quantitatively validating the EPR membrane docking structure and augmenting our understanding of the binding interface with atomic-level detail. Several observations and hypotheses reached from our MD simulations are also supported by experimental kinetic studies. Copyright © 2013 Elsevier Ltd. All rights reserved.

Band structure and orbital character of monolayer MoS2 with eleven-band tight-binding model

NASA Astrophysics Data System (ADS)

Shahriari, Majid; Ghalambor Dezfuli, Abdolmohammad; Sabaeian, Mohammad

2018-02-01

In this paper, based on a tight-binding (TB) model, first we present the calculations of eigenvalues as band structure and then present the eigenvectors as probability amplitude for finding electron in atomic orbitals for monolayer MoS2 in the first Brillouin zone. In these calculations we are considering hopping processes between the nearest-neighbor Mo-S, the next nearest-neighbor in-plan Mo-Mo, and the next nearest-neighbor in-plan and out-of-plan S-S atoms in a three-atom based unit cell of two-dimensional rhombic MoS2. The hopping integrals have been solved in terms of Slater-Koster and crystal field parameters. These parameters are calculated by comparing TB model with the density function theory (DFT) in the high-symmetry k-points (i.e. the K- and Γ-points). In our TB model all the 4d Mo orbitals and the 3p S orbitals are considered and detailed analysis of the orbital character of each energy level at the main high-symmetry points of the Brillouin zone is described. In comparison with DFT calculations, our results of TB model show a very good agreement for bands near the Fermi level. However for other bands which are far from the Fermi level, some discrepancies between our TB model and DFT calculations are observed. Upon the accuracy of Slater-Koster and crystal field parameters, on the contrary of DFT, our model provide enough accuracy to calculate all allowed transitions between energy bands that are very crucial for investigating the linear and nonlinear optical properties of monolayer MoS2.

Binding of /sup 18/F by cell membranes and cell walls of Streptococcus mutans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yotis, W.W.; Zeb, M.; McNulty, J.

1983-07-01

The binding of /sup 18/F to isolated cell membranes and cell walls of Streptococcus mutans GS-5 or other bacteria was assayed. The attachment of /sup 18/F to these cell envelopes proceeded slowly and reached equilibrium within 60 min. /sup 18/F binding was stimulated by Ca/sup 2 +/ (1 mM). The binding of /sup 18/F to cellular components was dependent upon the pH, as well as the amount of /sup 18/F and dose of the binder employed. The binding of /sup 18/F by cell walls prepared from fluoride-sensitive and fluoride-resistant cells of S. salivarius and S. mutans did not differ significantly.more » The pretreatment of cell walls or cell membranes for 60 min at 30 degrees C with 1 mg of RNase, DNase, or trypsin per ml did not influence the binding of /sup 18/F by the walls and membranes of S. mutans GS-5. However, prior exposure of cell membranes to sodium dodecyl sulfate caused a significant reduction in the number of /sup 18/F atoms bound by the membranes. In saturated assay systems, cell membranes of S. mutans GS-5 bound 10(15) to 10(16) atoms of /sup 18/F per mg (dry weight), whereas cell walls from S. mutans GS-5, FA-1, and HS-6 or Actinomyces viscosus T14V and T14AV bound 10(12) to 10(13) atoms of /sup 18/F per mg (dry weight). /sup 18/F in this quantity (10(12) to 10(13) atoms) cannot be detected with the fluoride electrode. The data provide, for the first time, a demonstration of /sup 18/F binding by cell membranes and walls of oral flora.« less

First-principles study of Ti intercalation between graphene and Au surface

NASA Astrophysics Data System (ADS)

Kaneko, T.; Imamura, H.

2011-06-01

We investigate the effects of Ti intercalation between graphene and Au surface on binding energy and charge doping by using the first-principles calculations. We show that the largest binding energy is realized by the intercalation of single mono-layer of Ti. We also show that electronic structure is very sensitive to the arrangement of metal atoms at the interface. If the composition of the interface layer is Ti0.33Au0.67 and the Ti is located at the top site, the Fermi level lies closely at the Dirac point, i.e., the Dirac cone of the ideal free-standing graphene is recovered.

Allosteric mechanism controls traffic in the chaperone/usher pathway.

PubMed

Di Yu, Xiao; Dubnovitsky, Anatoly; Pudney, Alex F; Macintyre, Sheila; Knight, Stefan D; Zavialov, Anton V

2012-11-07

Many virulence organelles of Gram-negative bacterial pathogens are assembled via the chaperone/usher pathway. The chaperone transports organelle subunits across the periplasm to the outer membrane usher, where they are released and incorporated into growing fibers. Here, we elucidate the mechanism of the usher-targeting step in assembly of the Yersinia pestis F1 capsule at the atomic level. The usher interacts almost exclusively with the chaperone in the chaperone:subunit complex. In free chaperone, a pair of conserved proline residues at the beginning of the subunit-binding loop form a "proline lock" that occludes the usher-binding surface and blocks usher binding. Binding of the subunit to the chaperone rotates the proline lock away from the usher-binding surface, allowing the chaperone-subunit complex to bind to the usher. We show that the proline lock exists in other chaperone/usher systems and represents a general allosteric mechanism for selective targeting of chaperone:subunit complexes to the usher and for release and recycling of the free chaperone. Copyright © 2012 Elsevier Ltd. All rights reserved.

Single-molecule imaging of DNA polymerase I (Klenow fragment) activity by atomic force microscopy

NASA Astrophysics Data System (ADS)

Chao, J.; Zhang, P.; Wang, Q.; Wu, N.; Zhang, F.; Hu, J.; Fan, C. H.; Li, B.

2016-03-01

We report a DNA origami-facilitated single-molecule platform that exploits atomic force microscopy to study DNA replication. We imaged several functional activities of the Klenow fragment of E. coli DNA polymerase I (KF) including binding, moving, and dissociation from the template DNA. Upon completion of these actions, a double-stranded DNA molecule was formed. Furthermore, the direction of KF activities was captured and then confirmed by shifting the KF binding sites on the template DNA.We report a DNA origami-facilitated single-molecule platform that exploits atomic force microscopy to study DNA replication. We imaged several functional activities of the Klenow fragment of E. coli DNA polymerase I (KF) including binding, moving, and dissociation from the template DNA. Upon completion of these actions, a double-stranded DNA molecule was formed. Furthermore, the direction of KF activities was captured and then confirmed by shifting the KF binding sites on the template DNA. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06544e

Computational Design of Ligand Binding Proteins with High Affinity and Selectivity

PubMed Central

Dou, Jiayi; Doyle, Lindsey; Nelson, Jorgen W.; Schena, Alberto; Jankowski, Wojciech; Kalodimos, Charalampos G.; Johnsson, Kai; Stoddard, Barry L.; Baker, David

2014-01-01

The ability to design proteins with high affinity and selectivity for any given small molecule would have numerous applications in biosensing, diagnostics, and therapeutics, and is a rigorous test of our understanding of the physiochemical principles that govern molecular recognition phenomena. Attempts to design ligand binding proteins have met with little success, however, and the computational design of precise molecular recognition between proteins and small molecules remains an “unsolved problem”1. We describe a general method for the computational design of small molecule binding sites with pre-organized hydrogen bonding and hydrophobic interfaces and high overall shape complementary to the ligand, and use it to design protein binding sites for the steroid digoxigenin (DIG). Of 17 designs that were experimentally characterized, two bind DIG; the highest affinity design has the lowest predicted interaction energy and the most pre-organized binding site in the set. A comprehensive binding-fitness landscape of this design generated by library selection and deep sequencing was used to guide optimization of binding affinity to a picomolar level, and two X-ray co-crystal structures of optimized complexes show atomic level agreement with the design models. The designed binder has a high selectivity for DIG over the related steroids digitoxigenin, progesterone, and β-estradiol, which can be reprogrammed through the designed hydrogen-bonding interactions. Taken together, the binding fitness landscape, co-crystal structures, and thermodynamic binding parameters illustrate how increases in binding affinity can result from distal sequence changes that limit the protein ensemble to conformers making the most energetically favorable interactions with the ligand. The computational design method presented here should enable the development of a new generation of biosensors, therapeutics, and diagnostics. PMID:24005320

Atomic Resolution Description of the Interaction between the Nucleoprotein and Phosphoprotein of Hendra Virus

PubMed Central

Yabukarski, Filip; Blocquel, David; Schneider, Robert; Tarbouriech, Nicolas; Papageorgiou, Nicolas; Ruigrok, Rob W. H.; Jamin, Marc; Jensen, Malene Ringkjøbing; Longhi, Sonia; Blackledge, Martin

2013-01-01

Hendra virus (HeV) is a recently emerged severe human pathogen that belongs to the Henipavirus genus within the Paramyxoviridae family. The HeV genome is encapsidated by the nucleoprotein (N) within a helical nucleocapsid. Recruitment of the viral polymerase onto the nucleocapsid template relies on the interaction between the C-terminal domain, NTAIL, of N and the C-terminal X domain, XD, of the polymerase co-factor phosphoprotein (P). Here, we provide an atomic resolution description of the intrinsically disordered NTAIL domain in its isolated state and in intact nucleocapsids using nuclear magnetic resonance (NMR) spectroscopy. Using electron microscopy, we show that HeV nucleocapsids form herringbone-like structures typical of paramyxoviruses. We also report the crystal structure of XD of P that consists of a three-helix bundle. We study the interaction between NTAIL and XD using NMR titration experiments and provide a detailed mapping of the reciprocal binding sites. We show that the interaction is accompanied by α-helical folding of the molecular recognition element of NTAIL upon binding to a hydrophobic patch on the surface of XD. Finally, using solution NMR, we investigate the interaction between intact nucleocapsids and XD. Our results indicate that monomeric XD binds to NTAIL without triggering an additional unwinding of the nucleocapsid template. The present results provide a structural description at the atomic level of the protein-protein interactions required for transcription and replication of HeV, and the first direct observation of the interaction between the X domain of P and intact nucleocapsids in Paramyxoviridae. PMID:24086133

Atomic resolution description of the interaction between the nucleoprotein and phosphoprotein of Hendra virus.

PubMed

Communie, Guillaume; Habchi, Johnny; Yabukarski, Filip; Blocquel, David; Schneider, Robert; Tarbouriech, Nicolas; Papageorgiou, Nicolas; Ruigrok, Rob W H; Jamin, Marc; Jensen, Malene Ringkjøbing; Longhi, Sonia; Blackledge, Martin

2013-01-01

Hendra virus (HeV) is a recently emerged severe human pathogen that belongs to the Henipavirus genus within the Paramyxoviridae family. The HeV genome is encapsidated by the nucleoprotein (N) within a helical nucleocapsid. Recruitment of the viral polymerase onto the nucleocapsid template relies on the interaction between the C-terminal domain, N(TAIL), of N and the C-terminal X domain, XD, of the polymerase co-factor phosphoprotein (P). Here, we provide an atomic resolution description of the intrinsically disordered N(TAIL) domain in its isolated state and in intact nucleocapsids using nuclear magnetic resonance (NMR) spectroscopy. Using electron microscopy, we show that HeV nucleocapsids form herringbone-like structures typical of paramyxoviruses. We also report the crystal structure of XD of P that consists of a three-helix bundle. We study the interaction between N(TAIL) and XD using NMR titration experiments and provide a detailed mapping of the reciprocal binding sites. We show that the interaction is accompanied by α-helical folding of the molecular recognition element of N(TAIL) upon binding to a hydrophobic patch on the surface of XD. Finally, using solution NMR, we investigate the interaction between intact nucleocapsids and XD. Our results indicate that monomeric XD binds to N(TAIL) without triggering an additional unwinding of the nucleocapsid template. The present results provide a structural description at the atomic level of the protein-protein interactions required for transcription and replication of HeV, and the first direct observation of the interaction between the X domain of P and intact nucleocapsids in Paramyxoviridae.

Computational redesign of a protein-protein interface for high affinity and binding specificity using modular architecture and naturally occurring template fragments.

PubMed

Potapov, V; Reichmann, D; Abramovich, R; Filchtinski, D; Zohar, N; Ben Halevy, D; Edelman, M; Sobolev, V; Schreiber, G

2008-12-05

A new method is presented for the redesign of protein-protein interfaces, resulting in specificity of the designed pair while maintaining high affinity. The design is based on modular interface architecture and was carried out on the interaction between TEM1 beta-lactamase and its inhibitor protein, beta-lactamase inhibitor protein. The interface between these two proteins is composed of several mostly independent modules. We previously showed that it is possible to delete a complete module without affecting the overall structure of the interface. Here, we replace a complete module with structure fragments taken from nonrelated proteins. Nature-optimized fragments were chosen from 10(7) starting templates found in the Protein Data Bank. A procedure was then developed to identify sets of interacting template residues with a backbone arrangement mimicking the original module. This generated a final list of 361 putative replacement modules that were ranked using a novel scoring function based on grouped atom-atom contact surface areas. The top-ranked designed complex exhibited an affinity of at least the wild-type level and a mode of binding that was remarkably specific despite the absence of negative design in the procedure. In retrospect, the combined application of three factors led to the success of the design approach: utilizing the modular construction of the interface, capitalizing on native rather than artificial templates, and ranking with an accurate atom-atom contact surface scoring function.

An experimental investigation of fractionation by sputter deposition. [application to solar wind irradiation of lunar soil

NASA Technical Reports Server (NTRS)

Paruso, D. M.; Cassidy, W. A.; Hapke, B. W.

1978-01-01

Artificial glass targets composed of elements varying widely in atomic weight were irradiated at an angle of incidence of 45 deg by 2-keV hydrogen ions at a current density of .33 mA/sq cm, and sputtered atoms were caught on a molybdenum film. Analyses of the sputter-deposited films and unsputtered target glasses were carried out by electron microprobe. The backward-sputtered component was found to be enriched in elements of low atomic weight, while the forward-sputtered component was enriched in heavy atoms. These results indicate that at the lunar surface lighter elements and isotopes would tend to be ejected in backward directions, escaping directly through the openings which admit bombarding ions without first striking an adjacent grain surface; heavy elements and isotopes would be forward-sputtered deeper into the soil and be preferentially retained, contributing to the reported enrichments of heavy elements and isotopes. Additional results show that the binding energy of an element in its oxide form influences the sticking coefficient of a sputtered atom; elements of low binding energy are likely to desorb, while elements of high binding energy tend to stick to the first bounce surface.

Interplay between Mechanics, Electronics, and Energetics in Atomic-Scale Junctions

NASA Astrophysics Data System (ADS)

Aradhya, Sriharsha V.

The physical properties of materials at the nanoscale are controlled to a large extent by their interfaces. While much knowledge has been acquired about the properties of material in the bulk, there are many new and interesting phenomena at the interfaces that remain to be better understood. This is especially true at the scale of their constituent building blocks - atoms and molecules. Studying materials at this intricate level is a necessity at this point in time because electronic devices are rapidly approaching the limits of what was once thought possible, both in terms of their miniaturization as well as our ability to design their behavior. In this thesis I present our explorations of the interplay between mechanical properties, electronic transport and binding energetics of single atomic contacts and single-molecule junctions. Experimentally, we use a customized conducting atomic force microscope (AFM) that simultaneously measures the current and force across atomic-scale junctions. We use this instrument to study single atomic contacts of gold and silver and single-molecule junctions formed in the gap between two gold metallic point contacts, with molecules with a variety of backbones and chemical linker groups. Combined with density functional theory based simulations and analytical modeling, these experiments provide insight into the correlations between mechanics and electronic structure at the atomic level. In carrying out these experimental studies, we repeatedly form and pull apart nanoscale junctions between a metallized AFM cantilever tip and a metal-coated substrate. The force and conductance of the contact are simultaneously measured as each junction evolves through a series of atomic-scale rearrangements and bond rupture events, frequently resulting in single atomic contacts before rupturing completely. The AFM is particularly optimized to achieve high force resolution with stiff probes that are necessary to create and measure forces across atomic-size junctions that are otherwise difficult to fabricate using conventional lithographic techniques. In addition to the instrumentation, we have developed new algorithmic routines to perform statistical analyses of force data, with varying degrees of reliance on the conductance signatures. The key results presented in this thesis include our measurements with gold metallic contacts, through which we are able to rigorously characterize the stiffness and maximum forces sustained by gold single atomic contacts and many different gold-molecule-gold single-molecule junctions. In our experiments with silver metallic contacts we use statistical correlations in conductance to distinguish between pristine and oxygen-contaminated silver single atomic contacts. This allows us to separately obtain mechanical information for each of these structural motifs. The independently measured force data also provides new insights about atomic-scale junctions that are not possible to obtain through conductance measurements alone. Using a systematically designed set of molecules, we are able to demonstrate that quantum interference is not quenched in single-molecule junctions even at room temperature and ambient conditions. We have also been successful in conducting one of the first quantitative measurements of van der Waals forces at the metal-molecule interface at the single-molecule level. Finally, towards the end of this thesis, we present a general analytical framework to quantitatively reconstruct the binding energy curves of atomic-scale junctions directly from experiments, thereby unifying all of our mechanical measurements. I conclude with a summary of the work presented in this thesis, and an outlook for potential future studies that could be guided by this work.

Aβ1-25-Derived Sphingolipid-Domain Tracer Peptide SBD Interacts with Membrane Ganglioside Clusters via a Coil-Helix-Coil Motif

PubMed Central

Wang, Yaofeng; Kraut, Rachel; Mu, Yuguang

2015-01-01

The Amyloid-β (Aβ)-derived, sphingolipid binding domain (SBD) peptide is a fluorescently tagged probe used to trace the diffusion behavior of sphingolipid-containing microdomains in cell membranes through binding to a constellation of glycosphingolipids, sphingomyelin, and cholesterol. However, the molecular details of the binding mechanism between SBD and plasma membrane domains remain unclear. Here, to investigate how the peptide recognizes the lipid surface at an atomically detailed level, SBD peptides in the environment of raft-like bilayers were examined in micro-seconds-long molecular dynamics simulations. We found that SBD adopted a coil-helix-coil structural motif, which binds to multiple GT1b gangliosides via salt bridges and CH–π interactions. Our simulation results demonstrate that the CH–π and electrostatic forces between SBD monomers and GT1b gangliosides clusters are the main driving forces in the binding process. The presence of the fluorescent dye and linker molecules do not change the binding mechanism of SBD probes with gangliosides, which involves the helix-turn-helix structural motif that was suggested to constitute a glycolipid binding domain common to some sphingolipid interacting proteins, including HIV gp120, prion, and Aβ. PMID:26540054

Partial Ionic Character beyond the Pauling Paradigm: Metal Nanoparticles

DOE PAGES

Duanmu, Kaining; Truhlar, Donald G.

2014-11-12

A canonical perspective on the chemical bond is the Pauling paradigm: a bond in a molecule containing only identical atoms has no ionic character. However, we show that homonuclear silver clusters have very uneven charge distributions (for example, the C 2v structure of Ag 4 has a larger dipole moment than formaldehyde or acetone), and we show how to predict the charge distribution from coordination numbers and Hirshfeld charges. The new charge model is validated against Kohn–Sham calculations of dipole moments with four approximations for the exchange–correlation functional. We report Kohn–Sham studies of the binding energies of CO on silvermore » monomer and silver clusters containing 2–18 atoms. We also find that an accurate charge model is essential for understanding the site dependence of binding. In particular we find that atoms with more positive charges tend to have higher binding energies, which can be used for guidance in catalyst modeling and design. Furthermore, the nonuniform charge distribution of silver clusters predisposes the site preference of binding of carbon monoxide, and we conclude that nonuniform charge distributions are an important property for understanding binding of metal nanoparticles in general.« less

Characterization of the allosteric binding pocket of human liver fructose-1,6-bisphosphatase by protein crystallography and inhibitor activity studies.

PubMed

Iversen, L F; Brzozowski, M; Hastrup, S; Hubbard, R; Kastrup, J S; Larsen, I K; Naerum, L; Nørskov-Lauridsen, L; Rasmussen, P B; Thim, L; Wiberg, F C; Lundgren, K

1997-05-01

The structures of three complexes of human fructose-1,6-bisphosphatase (FB) with the allosteric inhibitor AMP and two AMP analogues have been determined and all fully refined. The data used for structure determination were collected at cryogenic temperature (110 K), and with the use of synchrotron radiation. The structures reveal a common mode of binding for AMP and formycine monophosphate (FMP). 5-Amino-4-carboxamido-1 beta-D-5-phosphate-ribofuranosyl-1H-imidazole (AICAR-P) shows an unexpected mode of binding to FB, different from that of the other two ligands. The imidazole ring of AICAR-P is rotated 180 degrees compared to the AMP and FMP bases. This rotation results in a slightly different hydrogen bonding pattern and minor changes in the water structure in the binding pocket. Common features of binding are seen for the ribose and phosphate moieties of all three compounds. Although binding in a different mode, AICAR-P is still capable of making all the important interactions with the residues building the allosteric binding pocket. The IC50 values of AMP, FMP, and AICAR-P were determined to be 1.7, 1.4, and 20.9 microM, respectively. Thus, the approximately 10 times lower potency of AICAR-P is difficult to explain solely from the variations observed in the binding pocket. Only one water molecule in the allosteric binding pocket was found to be conserved in all four subunits in all three structures. This water molecule coordinates to a phosphate oxygen atom and the N7 atom of the AMP molecule, and to similarly situated atoms in the FMP and AICAR-P complexes. This implies an important role of the conserved water molecule in binding of the ligand.

Characterization of the allosteric binding pocket of human liver fructose-1,6-bisphosphatase by protein crystallography and inhibitor activity studies.

PubMed Central

Iversen, L. F.; Brzozowski, M.; Hastrup, S.; Hubbard, R.; Kastrup, J. S.; Larsen, I. K.; Naerum, L.; Nørskov-Lauridsen, L.; Rasmussen, P. B.; Thim, L.; Wiberg, F. C.; Lundgren, K.

1997-01-01

The structures of three complexes of human fructose-1,6-bisphosphatase (FB) with the allosteric inhibitor AMP and two AMP analogues have been determined and all fully refined. The data used for structure determination were collected at cryogenic temperature (110 K), and with the use of synchrotron radiation. The structures reveal a common mode of binding for AMP and formycine monophosphate (FMP). 5-Amino-4-carboxamido-1 beta-D-5-phosphate-ribofuranosyl-1H-imidazole (AICAR-P) shows an unexpected mode of binding to FB, different from that of the other two ligands. The imidazole ring of AICAR-P is rotated 180 degrees compared to the AMP and FMP bases. This rotation results in a slightly different hydrogen bonding pattern and minor changes in the water structure in the binding pocket. Common features of binding are seen for the ribose and phosphate moieties of all three compounds. Although binding in a different mode, AICAR-P is still capable of making all the important interactions with the residues building the allosteric binding pocket. The IC50 values of AMP, FMP, and AICAR-P were determined to be 1.7, 1.4, and 20.9 microM, respectively. Thus, the approximately 10 times lower potency of AICAR-P is difficult to explain solely from the variations observed in the binding pocket. Only one water molecule in the allosteric binding pocket was found to be conserved in all four subunits in all three structures. This water molecule coordinates to a phosphate oxygen atom and the N7 atom of the AMP molecule, and to similarly situated atoms in the FMP and AICAR-P complexes. This implies an important role of the conserved water molecule in binding of the ligand. PMID:9144768

Extended Graph-Based Models for Enhanced Similarity Search in Cavbase.

PubMed

Krotzky, Timo; Fober, Thomas; Hüllermeier, Eyke; Klebe, Gerhard

2014-01-01

To calculate similarities between molecular structures, measures based on the maximum common subgraph are frequently applied. For the comparison of protein binding sites, these measures are not fully appropriate since graphs representing binding sites on a detailed atomic level tend to get very large. In combination with an NP-hard problem, a large graph leads to a computationally demanding task. Therefore, for the comparison of binding sites, a less detailed coarse graph model is used building upon so-called pseudocenters. Consistently, a loss of structural data is caused since many atoms are discarded and no information about the shape of the binding site is considered. This is usually resolved by performing subsequent calculations based on additional information. These steps are usually quite expensive, making the whole approach very slow. The main drawback of a graph-based model solely based on pseudocenters, however, is the loss of information about the shape of the protein surface. In this study, we propose a novel and efficient modeling formalism that does not increase the size of the graph model compared to the original approach, but leads to graphs containing considerably more information assigned to the nodes. More specifically, additional descriptors considering surface characteristics are extracted from the local surface and attributed to the pseudocenters stored in Cavbase. These properties are evaluated as additional node labels, which lead to a gain of information and allow for much faster but still very accurate comparisons between different structures.

Characterization of sea cucumber (stichopus japonicus) ovum hydrolysates: calcium chelation, solubility and absorption into intestinal epithelial cells.

PubMed

Sun, Na; Cui, Pengbo; Lin, Songyi; Yu, Cuiping; Tang, Yue; Wei, Ye; Xiong, Youling; Wu, Haitao

2017-10-01

Sea cucumber (Stichopus japonicus) ovum hydrolysates (SCOHs) chelated with calcium were produced to investigate the characteristics of calcium binding and solubility, as well as to study any effects on calcium absorption by human intestinal epithelial cells. The results of the present study show that the calcium-binding capacity of SCOHs depended greatly on the type of proteases. The maximum level of Ca binding (0.38 mmol L -1 ) occurred when trypsin was used, with a peptide yield of 85.7%. Investigation of the possible chelating modes between SCOHs and calcium ions indicated that calcium ions bound to SCOHs primarily via interactions with carboxyl oxygen and amino nitrogen atoms of Glu and Asp and also that the phosphoserine residues might be also responsible for SCOH-calcium chelation. Moreover, SCOH-calcium complexes maintained the solubility of calcium under simulated gastrointestinal digestion, regardless of the presence of dietary components such as oxalate. Furthermore, SCOH-Ca led to higher peak intracellular [Ca 2+ ] i in both Caco-2 cells (338.3 nmol L -1 versus 269.6 nmol L -1 ) and HT-29 cells (373.9 nmol L -1 versus 271.7 nmol L -1 ) than casein phosphopeptide-Ca. Carboxyl oxygen and amino nitrogen atoms in the SCOHs could bind calcium ions, forming SCOH-calcium complexes. These complexes improved calcium solubility under simulated gastrointestinal digestion and also promoted calcium absorption in Caco-2 and HT-29 cells. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Principles for designing proteins with cavities formed by curved β sheets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marcos, Enrique; Basanta, Benjamin; Chidyausiku, Tamuka M.

Active sites and ligand-binding cavities in native proteins are often formed by curved β sheets, and the ability to control β-sheet curvature would allow design of binding proteins with cavities customized to specific ligands. Toward this end, we investigated the mechanisms controlling β-sheet curvature by studying the geometry of β sheets in naturally occurring protein structures and folding simulations. The principles emerging from this analysis were used to design, de novo, a series of proteins with curved β sheets topped with α helices. Nuclear magnetic resonance and crystal structures of the designs closely match the computational models, showing that β-sheetmore » curvature can be controlled with atomic-level accuracy. Our approach enables the design of proteins with cavities and provides a route to custom design ligand-binding and catalytic sites.« less

Hydrogen passivation and multiple hydrogen-Hg vacancy complex impurities (nH-VHg, n = 1,2,3,4) in Hg0.75Cd0.25Te

NASA Astrophysics Data System (ADS)

Xue, L.; Tang, D. H.; Qu, X. D.; Sun, L. Z.; Lu, Wei; Zhong, J. X.

2011-09-01

Using first-principles method within the framework of the density functional theory, we study the formation energies and the binding energies of multiple hydrogen-mercury vacancy complex impurities (nH-VHg, n = 1,2,3,4) in Hg0.75Cd0.25Te. We find that, when mercury vacancies exist in Hg0.75Cd0.25Te, the formation of the complex impurity between H and VHg (1H-VHg) is easy and its binding energy is up to 0.56 eV. In this case, the deep acceptor level of mercury vacancy is passivated. As the hydrogen concentration increases, we find that the complex impurity between VHg and two hydrogen atoms (2H-VHg) is more stable than 1H-VHg. This complex passivates both the two acceptor levels introduced by mercury vacancy and neutralizes the p-type dopant characteristics of VHg in Hg0.75Cd0.25Te. Moreover, we find that the complex impurities formed by one VHg and three or four H atoms (3H-VHg, 4H-VHg) are still stable in Hg0.75Cd0.25Te, changing the VHg doped p-type Hg0.75Cd0.25Te to n-type material.

Design of graphene nanoparticle undergoing axial compression: quantum study

NASA Astrophysics Data System (ADS)

Glukhova, O. E.; Kirillova, I. V.; Saliy, I. N.; Kolesnikova, A. S.; Slepchenkov, M. M.

2011-03-01

We report the results of quantum mechanical investigations of the atomic structure and deformations of graphene nanoparticle undergoing axial compression. We applied the tight-binding (TB) method. Our transferable tightbinding potential correctly reproduced tight-binding changes in the electronic configuration as a function of the local bonding geometry around each carbon atom. The tight-binding method applied provided the consideration and calculation of the rehybridization between σ- and π-orbitals. To research nanoribbons using tight-binding potential our own program was used. We adapted TB method to be able to run the algorithm on a parallel computing machine (computer cluster). To simulate axial compression of graphene nanoparticles the atoms on the ends were fixed on the plates. The plates were moved towards each other to decrease the length at some percent. Plane atomic network undergoing axial compression became wave-like. The amplitude of wave and its period were not constant and changed along axis. This is a phase transition. The strain energy collapse occurs at the value of axial compression 0.03-0.04. The strain energy increased up to the quantity compression 0.03, then collapsed sharply and decreased. So according to our theoretical investigation, the elasticity of graphene nanoparticles is more than the elasticity of nanotubes the same width and length. The curvature of the atomic network because of compression will decrease the reactivity of graphene nanoparticles. We have calculated the atomic structure and electronic structure of the compression graphene nanopaticle at each step of strain of axial compression. We have come to the conclusion that the wave-like graphenes adsorbing protein and nucleic acid are the effective nanosensors and bionanosensors.

Spatial Analysis and Quantification of the Thermodynamic Driving Forces in Protein-Ligand Binding: Binding Site Variability

PubMed Central

Raman, E. Prabhu; MacKerell, Alexander D.

2015-01-01

The thermodynamic driving forces behind small molecule-protein binding are still not well understood, including the variability of those forces associated with different types of ligands in different binding pockets. To better understand these phenomena we calculate spatially resolved thermodynamic contributions of the different molecular degrees of freedom for the binding of propane and methanol to multiple pockets on the proteins Factor Xa and p38 MAP kinase. Binding thermodynamics are computed using a statistical thermodynamics based end-point method applied on a canonical ensemble comprising the protein-ligand complexes and the corresponding free states in an explicit solvent environment. Energetic and entropic contributions of water and ligand degrees of freedom computed from the configurational ensemble provides an unprecedented level of detail into the mechanisms of binding. Direct protein-ligand interaction energies play a significant role in both non-polar and polar binding, which is comparable to water reorganization energy. Loss of interactions with water upon binding strongly compensates these contributions leading to relatively small binding enthalpies. For both solutes, the entropy of water reorganization is found to favor binding in agreement with the classical view of the “hydrophobic effect”. Depending on the specifics of the binding pocket, both energy-entropy compensation and reinforcement mechanisms are observed. Notable is the ability to visualize the spatial distribution of the thermodynamic contributions to binding at atomic resolution showing significant differences in the thermodynamic contributions of water to the binding of propane versus methanol. PMID:25625202

Adsorption in zeolites using mechanically embedded ONIOM clusters

DOE PAGES

Patet, Ryan E.; Caratzoulas, Stavros; Vlachos, Dionisios G.

2016-09-01

Here, we have explored mechanically embedded three-layer QM/QM/MM ONIOM models for computational studies of binding in Al-substituted zeolites. In all the models considered, the high-level-theory layer consists of the adsorbate molecule and of the framework atoms within the first two coordination spheres of the Al atom and is treated at the M06-2X/6-311G(2df,p) level. For simplicity, flexibility and routine applicability, the outer, low-level-theory layer is treated with the UFF. We have modelled the intermediate-level layer quantum mechanically and investigated the performance of HF theory and of three DFT functionals, B3LYP, M06-2X and ωB97x-D, for different layer sizes and various basis sets,more » with and without BSSE corrections. We have studied the binding of sixteen probe molecules in H-MFI and compared the computed adsorption enthalpies with published experimental data. We have demonstrated that HF and B3LYP are inadequate for the description of the interactions between the probe molecules and the framework surrounding the metal site of the zeolite on account of their inability to capture dispersion forces. Both M06-2X and ωB97x-D on average converge within ca. 10% of the experimental values. We have further demonstrated transferability of the approach by computing the binding enthalpies of n-alkanes (C1–C8) in H-MFI, H-BEA and H-FAU, with very satisfactory agreement with experiment. The computed entropies of adsorption of n-alkanes in H-MFI are also found to be in good agreement with experimental data. Finally, we compare with published adsorption energies calculated by periodic-DFT for n-C3 to n-C6 alkanes, water and methanol in H-ZSM-5 and find very good agreement.« less

First-principles study of structure, electronic properties and stability of tungsten adsorption on TiC(111) surface with disordered vacancies

NASA Astrophysics Data System (ADS)

Ilyasov, Victor V.; Pham, Khang D.; Zhdanova, Tatiana P.; Phuc, Huynh V.; Hieu, Nguyen N.; Nguyen, Chuong V.

2017-12-01

In this paper, we systematically investigate the atomic structure, electronic and thermodynamic properties of adsorbed W atoms on the polar Ti-terminated TixCy (111) surface with different configurations of adsorptions using first principle calculations. The bond length, adsorption energy, and formation energy for different reconstructions of the atomic structure of the W/TixCy (111) systems were established. The effect of the tungsten coverage on the electronic structure and the adsorption mechanism of tungsten atom on the TixCy (111) are also investigated. We also suggest the possible mechanisms of W nucleation on the TixCy (111) surface. The effective charges on W atoms and nearest-neighbor atoms in the examined reconstructions were identified. Additionally, we have established the charge transfer from titanium atom to tungsten and carbon atoms which determine by the reconstruction of the local atomic and electronic structures. Our calculations showed that the charge transfer correlates with the electronegativity of tungsten and nearest-neighbor atoms. We also determined the effective charge per atom of titanium, carbon atoms, and neighboring adsorbed tungsten atom in different binding configurations. We found that, with reduction of the lattice symmetry associated with titanium and carbon vacancies, the adsorption energy increases by 1.2 times in the binding site A of W/TixCy systems.

REVIEWS OF TOPICAL PROBLEMS: Properties of matter in ultrahigh magnetic fields and the structure of the surface of neutron stars

NASA Astrophysics Data System (ADS)

Liberman, Mikhail A.; Johansson, B.

1995-02-01

The physical properties of atoms, molecules, and solids in ultrahigh magnetic fields B gg 109 G that are believed to exist on the surface of neutron stars are discussed. In these fields, atoms are strongly deformed and elongated along the magnetic field lines; the binding energy and ionizing energy of the atoms are substantially increased and the interatomic interaction is dramatically changed. This strongly modifies the properties of matter at the surface of magnetic neutron stars which are crucial for modelling the pulsar magnetosphere. A scenario for magnetosphere evolution is proposed which suggests free emission for a young pulsar and strong binding of the matter to the surface at a later stage. This later stage is due to strongly bound chains of alternate heavy atoms and light atoms accreted on the surface of the star.

Modeling protein-small molecule interactions: structure and thermodynamics of noble gases binding in a cavity in mutant phage T4 lysozyme L99A.

PubMed

Mann, G; Hermans, J

2000-09-29

The complexes of phage T4 lysozyme L99A with noble gases have been studied by molecular dynamics simulation. In a long simulation of the complex with one Xe atom, the structure was found to undergo global conformation change involving a reversible opening and closing of the entrance to the substrate-binding site, during which the conformations of the N and C-terminal domains varied little. The distributions of Xe positions sampled in dynamics simulations were refined in terms of anisotropic Gaussian distributions via least-squares minimization of the difference between Fourier transforms. In addition, molecular transformation simulations have been applied in order to calculate the binding free energies of Xe, Kr and Ar relative to a standard state at a pressure of 1 bar. A single bound Xe is found to assume an equilibrium distribution over three adjacent preferred sites, while in a two-Xe complex, the two Xe atoms preferentially occupy two of these. The positions of the three sites agree closely with the positions of bound Xe determined in the refined crystal structure of a complex formed at a pressure of 8 bar Xe, and the calculated affinities agree well with the observed partial occupancies. At a pressure of 8 bar, a mixture of one-Xe and two-Xe complexes is present, and similarly for complexes with Kr and Ar, with single occupancy relatively more prevalent with Kr and Ar. (Binding of a third Xe atom is found to be quite unfavorable.) A comparison with simulation results for the binding of benzene to the same site leads to the conclusion that binding of Xe within cavities in proteins is common because of several favorable factors: (1) Xe has a large atomic polarizability; (2) Xe can be applied at a relatively high pressure, i.e. high chemical potential; (3) an unfavorable entropic term related to the need to orient the ligand in the binding site is absent. Finally, it is found that the model's binding energy of a water molecule in the cavity is insufficient to overcome the unfavorable binding entropy. Copyright 2000 Academic Press.

Lithium-decorated oxidized graphyne for hydrogen storage by first principles study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yan, Zeyu; Wang, Lang; Cheng, Julong

2014-11-07

The geometric stability and hydrogen storage capacity of Li decorated oxidized γ-graphyne are studied based on the first-principles calculations. It is found that oxygen atoms trend to bond with acetylenic carbons and form C=O double bonds on both sides of graphyne. The binding energy of single Li atom on oxidized graphyne is 3.29 eV, owning to the strong interaction between Li atom and O atom. Meanwhile, the dispersion of Li is stable even under a relatively high density. One attached Li atom can at least adsorb six hydrogen molecules around. Benefitting from the porous structure of graphyne and the high attachedmore » Li density, a maximum hydrogen storage density 12.03 wt. % is achieved with four Li atoms in graphyne cell. The corresponding average binding energy is 0.24 eV/H{sub 2}, which is suitable for reversible storage. These results indicate that Li decorated graphyne can serve as a promising hydrogen storage material.« less

Specific Interactions of Antitumor Metallocenes with Deoxydinucleoside Monophosphates

NASA Astrophysics Data System (ADS)

Eberle, Rahel P.; Hari, Yvonne; Schürch, Stefan

2017-09-01

Bent metallocenes Cp2MCl2 (M = Ti, V, Nb, Mo) are known to exhibit cytotoxic activity against a variety of cancer types. Though the mechanism of action is not fully understood yet, the accumulation of the metal ions in the nucleus points towards DNA as one of the primary targets. A set of eight deoxydinucleoside monophosphates was used to study the adduct yields with metallocenes and cisplatin. The binding affinities are reflected by the relative intensities of the adducts and were found to follow the order of Pt > V > Ti > Mo (no adducts were detected with Nb). High-resolution tandem mass spectrometry was applied to locate the binding patterns in the deoxydinucleoside monophosphates. Whereas cisplatin binds to the soft nitrogen atoms in the purine nucleobases, the metallocenes additionally interact with the hard phosphate oxygen, which is in good agreement with the hard and soft (Lewis) acids and bases (HSAB) concept. However, the binding specificities were found to be unique for each metallocene. The hard Lewis acids titanium and vanadium predominantly bind to the deprotonated phosphate oxygen, whereas molybdenum, an intermediate Lewis acid, preferentially interacts with the nucleobases. Nucleobases comprise alternative binding sites for titanium and vanadium, presumably oxygen atoms for the first and nitrogen atoms for the latter. In summary, the intrinsic binding behavior of the different metallodrugs is reflected by the gas-phase dissociation of the adducts. Consequently, MS/MS can provide insights into therapeutically relevant interactions between metallodrugs and their cellular targets. [Figure not available: see fulltext.

The Strength of Hydrogen Bonds between Fluoro-Organics and Alcohols, a Theoretical Study.

PubMed

Rosenberg, Robert E

2018-05-10

Fluorinated organic compounds are ubiquitous in the pharmaceutical and agricultural industries. To better discern the mode of action of these compounds, it is critical to understand the strengths of hydrogen bonds involving fluorine. There are only a few published examples of the strengths of these bonds. This study provides a high level ab initio study of inter- and intramolecular hydrogen bonds between RF and R'OH, where R and R' are aryl, vinyl, alkyl, and cycloalkyl. Intermolecular binding energies average near 5 kcal/mol, while intramolecular binding energies average about 3 kcal/mol. Inclusion of zero-point energies and applying a counterpoise correction lessen the difference. In both series, modest increases in binding energies are seen with increased acidity of R'OH and increased electron donation of R in RF. In the intramolecular compounds, binding energy increases with the rigidity of the F-(C) n -OH ring. Inclusion of free energy corrections at 298 K results in exoergic binding energies for the intramolecular compounds and endoergic binding energies for the intermolecular compounds. Parameters such as bond lengths, vibrational frequencies, and atomic populations are consistent with formation of a hydrogen bond and with slightly stronger binding in the intermolecular cases over the intramolecular cases. However, these parameters correlated poorly with binding energies.

Binding of anticancer drug daunomycin to a TGGGGT G-quadruplex DNA probed by all-atom molecular dynamics simulations: additional pure groove binding mode and implications on designing more selective G-quadruplex ligands.

PubMed

Shen, Zhanhang; Mulholland, Kelly A; Zheng, Yujun; Wu, Chun

2017-09-01

DNA G-quadruplex structures are emerging cancer-specific targets for chemotherapeutics. Ligands that bind to and stabilize DNA G-quadruplexes have the potential to be anti-cancer drugs. Lack of binding selectivity to DNA G-quadruplex over DNA duplex remains a major challenge when attempting to develop G-quadruplex ligands into successful anti-cancer drugs. Thorough understanding of the binding nature of existing non-selective ligands that bind to both DNA quadruplex and DNA duplex will help to address this challenge. Daunomycin and doxorubicin, two commonly used anticancer drugs, are examples of non-selective DNA ligands. In this study, we extended our early all-atom binding simulation studies between doxorubicin and a DNA duplex (d(CGATCG) 2 ) to probe the binding between daunomycin and a parallel DNA quadruplex (d(TGGGGT) 4 ) and DNA duplex. In addition to the end stacking mode, which mimics the mode in the crystal structure, a pure groove binding mode was observed in our free binding simulations. The dynamic and energetic properties of these two binding modes are thoroughly examined, and a detailed comparison is made between DNA quadruplex binding modes and DNA duplex binding modes. Implications on the design of more selective DNA quadruplex ligands are also discussed. Graphical abstract Top stacking and groov binding modes from the MD simulations.

The binding of calcium ions by erythrocytes and `ghost'-cell membranes

PubMed Central

Long, C.; Mouat, Barbara

1971-01-01

1. Washed human erythrocytes, suspended in iso-osmotic sucrose containing 2.5mm-calcium chloride, bind about 400μg-atoms of calcium/litre of packed cells. Sucrose may be replaced by other sugars. 2. Partial replacement of sucrose by iso-osmotic potassium chloride diminishes the uptake of calcium, 50% inhibition occurring at about 50mm-potassium chloride. 3. Other univalent cations behave like potassium, whereas bivalent cations are much more inhibitory. The tervalent cations, yttrium and lanthanum, however, are the most effective inhibitors of calcium uptake. 4. An approximate correlation exists between the calcium uptake and the sialic acid content of erythrocytes of various species and of human erythrocytes that have been partially depleted of sialic acid by treatment with neuraminidase. However, even after complete removal of sialic acid, human erythrocytes still bind about 140μg-atoms of calcium/litre of packed cells. 5. A Scatchard (1949) plot of calcium uptake at various Ca2+ concentrations in the suspending media shows the presence of three different binding sites on the external surface of the human erythrocyte membrane. 6. Erythrocyte `ghost' cells, the membranes of which appear to be permeable to Ca2+ ions, can bind about 1000μg-atoms of calcium per `ghost'-cell equivalent of 1 litre of packed erythrocytes. This indicates that there are also binding sites for calcium on the internal surface of the erythrocyte membrane. PMID:5124387

Surface Passivation in Empirical Tight Binding

NASA Astrophysics Data System (ADS)

He, Yu; Tan, Yaohua; Jiang, Zhengping; Povolotskyi, Michael; Klimeck, Gerhard; Kubis, Tillmann

2016-03-01

Empirical Tight Binding (TB) methods are widely used in atomistic device simulations. Existing TB methods to passivate dangling bonds fall into two categories: 1) Method that explicitly includes passivation atoms is limited to passivation with atoms and small molecules only. 2) Method that implicitly incorporates passivation does not distinguish passivation atom types. This work introduces an implicit passivation method that is applicable to any passivation scenario with appropriate parameters. This method is applied to a Si quantum well and a Si ultra-thin body transistor oxidized with SiO2 in several oxidation configurations. Comparison with ab-initio results and experiments verifies the presented method. Oxidation configurations that severely hamper the transistor performance are identified. It is also shown that the commonly used implicit H atom passivation overestimates the transistor performance.

The effect of cigarette smoke extract on thrombomodulin-thrombin binding: an atomic force microscopy study.

PubMed

Wei, Yujie; Zhang, Xuejie; Xu, Li; Yi, Shaoqiong; Li, Yi; Fang, Xiaohong; Liu, Huiliang

2012-10-01

Cigarette smoking is a well-known risk factor for cardiovascular disease. Smoking can cause vascular endothelial dysfunction and consequently trigger haemostatic activation and thrombosis. However, the mechanism of how smoking promotes thrombosis is not fully understood. Thrombosis is associated with the imbalance of the coagulant system due to endothelial dysfunction. As a vital anticoagulation cofactor, thrombomodulin (TM) located on the endothelial cell surface is able to regulate intravascular coagulation by binding to thrombin, and the binding results in thrombosis inhibition. This work focused on the effects of cigarette smoke extract (CSE) on TM-thrombin binding by atomic force microscopy (AFM) based single-molecule force spectroscopy. The results from both in vitro and live-cell experiments indicated that CSE could notably reduce the binding probability of TM and thrombin. This study provided a new approach and new evidence for studying the mechanism of thrombosis triggered by cigarette smoking.

Enhanced sampling simulations to construct free-energy landscape of protein-partner substrate interaction.

PubMed

Ikebe, Jinzen; Umezawa, Koji; Higo, Junichi

2016-03-01

Molecular dynamics (MD) simulations using all-atom and explicit solvent models provide valuable information on the detailed behavior of protein-partner substrate binding at the atomic level. As the power of computational resources increase, MD simulations are being used more widely and easily. However, it is still difficult to investigate the thermodynamic properties of protein-partner substrate binding and protein folding with conventional MD simulations. Enhanced sampling methods have been developed to sample conformations that reflect equilibrium conditions in a more efficient manner than conventional MD simulations, thereby allowing the construction of accurate free-energy landscapes. In this review, we discuss these enhanced sampling methods using a series of case-by-case examples. In particular, we review enhanced sampling methods conforming to trivial trajectory parallelization, virtual-system coupled multicanonical MD, and adaptive lambda square dynamics. These methods have been recently developed based on the existing method of multicanonical MD simulation. Their applications are reviewed with an emphasis on describing their practical implementation. In our concluding remarks we explore extensions of the enhanced sampling methods that may allow for even more efficient sampling.

Noncontiguous atom matching structural similarity function.

PubMed

Teixeira, Ana L; Falcao, Andre O

2013-10-28

Measuring similarity between molecules is a fundamental problem in cheminformatics. Given that similar molecules tend to have similar physical, chemical, and biological properties, the notion of molecular similarity plays an important role in the exploration of molecular data sets, query-retrieval in molecular databases, and in structure-property/activity modeling. Various methods to define structural similarity between molecules are available in the literature, but so far none has been used with consistent and reliable results for all situations. We propose a new similarity method based on atom alignment for the analysis of structural similarity between molecules. This method is based on the comparison of the bonding profiles of atoms on comparable molecules, including features that are seldom found in other structural or graph matching approaches like chirality or double bond stereoisomerism. The similarity measure is then defined on the annotated molecular graph, based on an iterative directed graph similarity procedure and optimal atom alignment between atoms using a pairwise matching algorithm. With the proposed approach the similarities detected are more intuitively understood because similar atoms in the molecules are explicitly shown. This noncontiguous atom matching structural similarity method (NAMS) was tested and compared with one of the most widely used similarity methods (fingerprint-based similarity) using three difficult data sets with different characteristics. Despite having a higher computational cost, the method performed well being able to distinguish either different or very similar hydrocarbons that were indistinguishable using a fingerprint-based approach. NAMS also verified the similarity principle using a data set of structurally similar steroids with differences in the binding affinity to the corticosteroid binding globulin receptor by showing that pairs of steroids with a high degree of similarity (>80%) tend to have smaller differences in the absolute value of binding activity. Using a highly diverse set of compounds with information about the monoamine oxidase inhibition level, the method was also able to recover a significantly higher average fraction of active compounds when the seed is active for different cutoff threshold values of similarity. Particularly, for the cutoff threshold values of 86%, 93%, and 96.5%, NAMS was able to recover a fraction of actives of 0.57, 0.63, and 0.83, respectively, while the fingerprint-based approach was able to recover a fraction of actives of 0.41, 0.40, and 0.39, respectively. NAMS is made available freely for the whole community in a simple Web based tool as well as the Python source code at http://nams.lasige.di.fc.ul.pt/.

Identifying Interactions that Determine Fragment Binding at Protein Hotspots.

PubMed

Radoux, Chris J; Olsson, Tjelvar S G; Pitt, Will R; Groom, Colin R; Blundell, Tom L

2016-05-12

Locating a ligand-binding site is an important first step in structure-guided drug discovery, but current methods do little to suggest which interactions within a pocket are the most important for binding. Here we illustrate a method that samples atomic hotspots with simple molecular probes to produce fragment hotspot maps. These maps specifically highlight fragment-binding sites and their corresponding pharmacophores. For ligand-bound structures, they provide an intuitive visual guide within the binding site, directing medicinal chemists where to grow the molecule and alerting them to suboptimal interactions within the original hit. The fragment hotspot map calculation is validated using experimental binding positions of 21 fragments and subsequent lead molecules. The ligands are found in high scoring areas of the fragment hotspot maps, with fragment atoms having a median percentage rank of 97%. Protein kinase B and pantothenate synthetase are examined in detail. In each case, the fragment hotspot maps are able to rationalize a Free-Wilson analysis of SAR data from a fragment-based drug design project.

Metallothionein-like multinuclear clusters of mercury(II) and sulfur in peat

USGS Publications Warehouse

Nagy, K.L.; Manceau, A.; Gasper, J.D.; Ryan, J.N.; Aiken, G.R.

2011-01-01

Strong mercury(II)-sulfur (Hg-SR) bonds in natural organic matter, which influence mercury bioavailability, are difficult to characterize. We report evidence for two new Hg-SR structures using X-ray absorption spectroscopy in peats from the Florida Everglades with added Hg. The first, observed at a mole ratio of organic reduced S to Hg (Sred/Hg) between 220 and 1140, is a Hg4Sx type of cluster with each Hg atom bonded to two S atoms at 2.34 ?? and one S at 2.53 ??, and all Hg atoms 4.12 ?? apart. This model structure matches those of metal-thiolate clusters in metallothioneins, but not those of HgS minerals. The second, with one S atom at 2.34 ?? and about six C atoms at 2.97 to 3.28 ??, occurred at S red/Hg between 0.80 and 4.3 and suggests Hg binding to a thiolated aromatic unit. The multinuclear Hg cluster indicates a strong binding environment to cysteinyl sulfur that might impede methylation. Along with a linear Hg(SR)2 unit with Hg - S bond lengths of 2.34 ?? at Sred/Hg of about 10 to 20, the new structures support a continuum in Hg-SR binding strength in natural organic matter. ?? 2011 American Chemical Society.

Crystal structure of rofecoxib bound to human cyclooxygenase-2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orlando, Benjamin J.; Malkowski, Michael G.

2016-10-26

Rofecoxib (Vioxx) was one of the first selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) to be approved for use in humans. Within five years after its release to the public, Vioxx was withdrawn from the market owing to the adverse cardiovascular effects of the drug. Despite the widespread knowledge of the development and withdrawal of Vioxx, relatively little is known at the molecular level about how the inhibitor binds to COX-2. Vioxx is unique in that the inhibitor contains a methyl sulfone moiety in place of the sulfonamide moiety found in other coxibs such as celecoxib and valdecoxib. Here, new crystallization conditionsmore » were identified that allowed the structural determination of human COX-2 in complex with Vioxx and the structure was subsequently determined to 2.7- Å resolution. The crystal structure provides the first atomic level details of the binding of Vioxx to COX-2. As anticipated, Vioxx binds with its methyl sulfone moiety located in the side pocket of the cyclooxygenase channel, providing support for the isoform selectivity of this drug.« less

Free-energy simulations reveal that both hydrophobic and polar interactions are important for influenza hemagglutinin antibody binding.

PubMed

Xia, Zhen; Huynh, Tien; Kang, Seung-gu; Zhou, Ruhong

2012-03-21

Antibodies binding to conserved epitopes can provide a broad range of neutralization to existing influenza subtypes and may also prevent the propagation of potential pandemic viruses by fighting against emerging strands. Here we propose a computational framework to study structural binding patterns and detailed molecular mechanisms of viral surface glycoprotein hemagglutinin (HA) binding with a broad spectrum of neutralizing monoclonal antibody fragments (Fab). We used rigorous free-energy perturbation (FEP) methods to calculate the antigen-antibody binding affinities, with an aggregate underlying molecular-dynamics simulation time of several microseconds (∼2 μs) using all-atom, explicit-solvent models. We achieved a high accuracy in the validation of our FEP protocol against a series of known binding affinities for this complex system, with <0.5 kcal/mol errors on average. We then introduced what to our knowledge are novel mutations into the interfacial region to further study the binding mechanism. We found that the stacking interaction between Trp-21 in HA2 and Phe-55 in the CDR-H2 of Fab is crucial to the antibody-antigen association. A single mutation of either W21A or F55A can cause a binding affinity decrease of ΔΔG > 4.0 kcal/mol (equivalent to an ∼1000-fold increase in the dissociation constant K(d)). Moreover, for group 1 HA subtypes (which include both the H1N1 swine flu and the H5N1 bird flu), the relative binding affinities change only slightly (< ±1 kcal/mol) when nonpolar residues at the αA helix of HA mutate to conservative amino acids of similar size, which explains the broad neutralization capability of antibodies such as F10 and CR6261. Finally, we found that the hydrogen-bonding network between His-38 (in HA1) and Ser-30/Gln-64 (in Fab) is important for preserving the strong binding of Fab against group 1 HAs, whereas the lack of such hydrogen bonds with Asn-38 in most group 2 HAs may be responsible for the escape of antibody neutralization. These large-scale simulations may provide new insight into the antigen-antibody binding mechanism at the atomic level, which could be essential for designing more-effective vaccines for influenza. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Experimental design, modeling and optimization of polyplex formation between DNA oligonucleotides and branched polyethylenimine.

PubMed

Clima, Lilia; Ursu, Elena L; Cojocaru, Corneliu; Rotaru, Alexandru; Barboiu, Mihail; Pinteala, Mariana

2015-09-28

The complexes formed by DNA and polycations have received great attention owing to their potential application in gene therapy. In this study, the binding efficiency between double-stranded oligonucleotides (dsDNA) and branched polyethylenimine (B-PEI) has been quantified by processing of the images captured from the gel electrophoresis assays. The central composite experimental design has been employed to investigate the effects of controllable factors on the binding efficiency. On the basis of experimental data and the response surface methodology, a multivariate regression model has been constructed and statistically validated. The model has enabled us to predict the binding efficiency depending on experimental factors, such as concentrations of dsDNA and B-PEI as well as the initial pH of solution. The optimization of the binding process has been performed using simplex and gradient methods. The optimal conditions determined for polyplex formation have yielded a maximal binding efficiency close to 100%. In order to reveal the mechanism of complex formation at the atomic-scale, a molecular dynamic simulation has been carried out. According to the computation results, B-PEI amine hydrogen atoms have interacted with oxygen atoms from dsDNA phosphate groups. These interactions have led to the formation of hydrogen bonds between macromolecules, stabilizing the polyplex structure.

Interfacial metal and antibody recognition.

PubMed

Zhou, Tongqing; Hamer, Dean H; Hendrickson, Wayne A; Sattentau, Quentin J; Kwong, Peter D

2005-10-11

The unique ligation properties of metal ions are widely exploited by proteins, with approximately one-third of all proteins estimated to be metalloproteins. Although antibodies use various mechanisms for recognition, to our knowledge, none has ever been characterized that uses an interfacial metal. We previously described a family of CD4-reactive antibodies, the archetype being Q425. CD4:Q425 engagement does not interfere with CD4:HIV-1 gp120 envelope glycoprotein binding, but it blocks subsequent steps required for viral entry. Here, we use surface-plasmon resonance to show that Q425 requires calcium for recognition of CD4. Specifically, Q425 binding of calcium resulted in a 55,000-fold enhancement in affinity for CD4. X-ray crystallographic analyses of Q425 in the presence of Ca(2+), Ba(2+), or EDTA revealed an exposed metal-binding site, partially coordinated by five atoms contributed from four antibody complementarity-determining regions. The results suggest that Q425 recognition of CD4 involves direct ligation of antigen by the Q425-held calcium, with calcium binding each ligating atom of CD4 with approximately 1.5 kcal/mol of binding energy. This energetic contribution, which is greater than that from a typical protein atom, demonstrates how interfacial metal ligation can play a unique role in antigen recognition.

Interfacial metal and antibody recognition

PubMed Central

Zhou, Tongqing; Hamer, Dean H.; Hendrickson, Wayne A.; Sattentau, Quentin J.; Kwong, Peter D.

2005-01-01

The unique ligation properties of metal ions are widely exploited by proteins, with approximately one-third of all proteins estimated to be metalloproteins. Although antibodies use various mechanisms for recognition, to our knowledge, none has ever been characterized that uses an interfacial metal. We previously described a family of CD4-reactive antibodies, the archetype being Q425. CD4:Q425 engagement does not interfere with CD4:HIV-1 gp120 envelope glycoprotein binding, but it blocks subsequent steps required for viral entry. Here, we use surface-plasmon resonance to show that Q425 requires calcium for recognition of CD4. Specifically, Q425 binding of calcium resulted in a 55,000-fold enhancement in affinity for CD4. X-ray crystallographic analyses of Q425 in the presence of Ca2+, Ba2+, or EDTA revealed an exposed metal-binding site, partially coordinated by five atoms contributed from four antibody complementarity-determining regions. The results suggest that Q425 recognition of CD4 involves direct ligation of antigen by the Q425-held calcium, with calcium binding each ligating atom of CD4 with ≈1.5 kcal/mol of binding energy. This energetic contribution, which is greater than that from a typical protein atom, demonstrates how interfacial metal ligation can play a unique role in antigen recognition. PMID:16195378

Tight-binding study of Si2Cn (n = 3 to 42) fullerene-like or nanodiamonds microclusters: are Si atoms isolated or adjacent?

NASA Astrophysics Data System (ADS)

Leleyter, M.; Olivi-Tran, N.

2008-12-01

We studied in tight-binding approximation involving spν hybridization (ν=2,3), some Si2Cn (n=3 to 42) microclusters. We then investigated, on one hand, fragments of fullerene-like structures (sp2), and on the other hand, nanodiamonds (sp3) of adamantane-type or a 44-atom nanodiamond (with 2 inner atoms which are assumed to play the role of bulk atoms). We compared the stabilities, i.e. the electronic energies of these clusters, according to the various positions of the 2 Si atoms. Results are very different in the two kinds of hybridization. Besides, they can be analysed according to two different points of view: either the clusters are considered as small particles with limited sizes, or they are assumed to be used as models in order to simulate the Si-atom behaviour in very larger systems. In sp2 hybridization (fullerene-like geometries), the most stable isomer is always encountered when the 2 Si atoms build a Si2 group, and this result holds for both viewpoints quoted above. Conversely, in sp3 hybridization (nanodiamonds), since Si atoms “prefer” sites having the minimum connectivity, they are never found in adjacent sites. We see that with a simple and fast computational method we can explain an experimental fact which is very interesting such as the relative position of two heteroatoms in the cluster. This enhances the generality and the fecondity in the tight binding approximation due essentially to the link between this model and the graph theory, link based on the topology of the clusters.

How many atoms are required to characterize accurately trajectory fluctuations of a protein?

NASA Astrophysics Data System (ADS)

Cukier, Robert I.

2010-06-01

Large molecules, whose thermal fluctuations sample a complex energy landscape, exhibit motions on an extended range of space and time scales. Principal component analysis (PCA) is often used to extract dominant motions that in proteins are typically domain motions. These motions are captured in the large eigenvalue (leading) principal components. There is also information in the small eigenvalues, arising from approximate linear dependencies among the coordinates. These linear dependencies suggest that instead of using all the atom coordinates to represent a trajectory, it should be possible to use a reduced set of coordinates with little loss in the information captured by the large eigenvalue principal components. In this work, methods that can monitor the correlation (overlap) between a reduced set of atoms and any number of retained principal components are introduced. For application to trajectory data generated by simulations, where the overall translational and rotational motion needs to be eliminated before PCA is carried out, some difficulties with the overlap measures arise and methods are developed to overcome them. The overlap measures are evaluated for a trajectory generated by molecular dynamics for the protein adenylate kinase, which consists of a stable, core domain, and two more mobile domains, referred to as the LID domain and the AMP-binding domain. The use of reduced sets corresponding, for the smallest set, to one-eighth of the alpha carbon (CA) atoms relative to using all the CA atoms is shown to predict the dominant motions of adenylate kinase. The overlap between using all the CA atoms and all the backbone atoms is essentially unity for a sum over PCA modes that effectively capture the exact trajectory. A reduction to a few atoms (three in the LID and three in the AMP-binding domain) shows that at least the first principal component, characterizing a large part of the LID-binding and AMP-binding motion, is well described. Based on these results, the overlap criterion should be applicable as a guide to postulating and validating coarse-grained descriptions of generic biomolecular assemblies.

Exploration of the effect of sequence variations located inside the binding pocket of HIV-1 and HIV-2 proteases.

PubMed

Triki, Dhoha; Billot, Telli; Visseaux, Benoit; Descamps, Diane; Flatters, Delphine; Camproux, Anne-Claude; Regad, Leslie

2018-04-10

HIV-2 protease (PR2) is naturally resistant to most FDA (Food and Drug Administration)-approved HIV-1 protease inhibitors (PIs), a major antiretroviral class. In this study, we compared the PR1 and PR2 binding pockets extracted from structures complexed with 12 ligands. The comparison of PR1 and PR2 pocket properties showed that bound PR2 pockets were more hydrophobic with more oxygen atoms and fewer nitrogen atoms than PR1 pockets. The structural comparison of PR1 and PR2 pockets highlighted structural changes induced by their sequence variations and that were consistent with these property changes. Specifically, substitutions at residues 31, 46, and 82 induced structural changes in their main-chain atoms that could affect PI binding in PR2. In addition, the modelling of PR1 mutant structures containing V32I and L76M substitutions revealed a cooperative mechanism leading to structural deformation of flap-residue 45 that could modify PR2 flexibility. Our results suggest that substitutions in the PR1 and PR2 pockets can modify PI binding and flap flexibility, which could underlie PR2 resistance against PIs. These results provide new insights concerning the structural changes induced by PR1 and PR2 pocket variation changes, improving the understanding of the atomic mechanism of PR2 resistance to PIs.

Spectra of helium clusters with up to six atoms using soft-core potentials

NASA Astrophysics Data System (ADS)

Gattobigio, M.; Kievsky, A.; Viviani, M.

2011-11-01

In this paper, we investigate small clusters of helium atoms using the hyperspherical harmonic basis. We consider systems with A=2,3,4,5,6 atoms with an interparticle potential which does not present a strong repulsion at short distances. We use an attractive Gaussian potential that reproduces the values of the dimer binding energy, the atom-atom scattering length, and the effective range obtained with one of the widely used He-He interactions, the Aziz and Slaman potential, called LM2M2. In systems with more than two atoms, we consider a repulsive three-body force that, by construction, reproduces the trimer binding energy of the LM2M2 potential. With this model, consisting of the sum of a two- and three-body potential, we have calculated the spectrum of clusters formed by four, five, and six helium atoms. We have found that these systems present two bound states, one deep and one shallow, close to the threshold fixed by the energy of the (A-1)-atom system. Universal relations between the energies of the excited state of the A-atom system and the ground-state energy of the (A-1)-atom system are extracted, as well as the ratio between the ground state of the A-atom system and the ground-state energy of the trimer.

IgGs are made for walking on bacterial and viral surfaces

NASA Astrophysics Data System (ADS)

Preiner, Johannes; Kodera, Noriyuki; Tang, Jilin; Ebner, Andreas; Brameshuber, Mario; Blaas, Dieter; Gelbmann, Nicola; Gruber, Hermann J.; Ando, Toshio; Hinterdorfer, Peter

2014-07-01

Binding of antibodies to their cognate antigens is fundamental for adaptive immunity. Molecular engineering of antibodies for therapeutic and diagnostic purposes emerges to be one of the major technologies in combating many human diseases. Despite its importance, a detailed description of the nanomechanical process of antibody-antigen binding and dissociation on the molecular level is lacking. Here we utilize high-speed atomic force microscopy to examine the dynamics of antibody recognition and uncover a principle; antibodies do not remain stationary on surfaces of regularly spaced epitopes; they rather exhibit ‘bipedal’ stochastic walking. As monovalent Fab fragments do not move, steric strain is identified as the origin of short-lived bivalent binding. Walking antibodies gather in transient clusters that might serve as docking sites for the complement system and/or phagocytes. Our findings could inspire the rational design of antibodies and multivalent receptors to exploit/inhibit steric strain-induced dynamic effects.

Interaction of fluorescent sensor with superparamagnetic iron oxide nanoparticles.

PubMed

Karunakaran, Chockalingam; Jayabharathi, Jayaraman; Sathishkumar, Ramalingam; Jayamoorthy, Karunamoorthy

2013-06-01

To sense superparamagnetic iron oxides (Fe2O3 and Fe3O4) nanocrystals a sensitive bioactive phenanthroimidazole based fluorescent molecule, 2-(4-fluorophenyl)-1-phenyl-1H-phenanthro [9,10-d] imidazole has been designed and synthesized. Electronic spectral studies show that phenanthroimidazole is bound to the surface of iron oxide semiconductors. Fluorescent enhancement has been explained on the basis of photo-induced electron transfer (PET) mechanism and apparent binding constants have been deduced. Binding of phenanthroimidazole with iron oxide nanoparticles lowers the HOMO and LUMO energy levels of phenanthroimidazole molecule. Chemical affinity between the nitrogen atom of the phenanthroimidazole and Fe(2+) and Fe(3+) ions on the surface of the nano-oxide may result in strong binding of the phenanthroimidazole derivative with the nanoparticles. The electron injection from the photoexcited phenanthroimidazole to the iron oxides conduction band explains the enhanced fluorescence. Copyright © 2013 Elsevier B.V. All rights reserved.

Comparison of the bonding between ML(+) and ML2(+) (M = metal, L = noble gas)

NASA Technical Reports Server (NTRS)

Bauschlicher, Charles W., Jr.; Partridge, Harry; Langhoff, Stephen R.

1990-01-01

Ab initio calculations are reported of the spectroscopic constants for the low-lying states of the molecular ions ML2(+), where M = Li, Na, Mg, V, Fe, Co, Ni and Cu, and where L is usually Ar. Comparison with existing analogous calculations on the ML(+) ions shows how the bonding and binding energy change with the addition of a second noble gas atom. The second binding energy is predicted to be essentially the same as the first for the Li, Na, Mg, and V ions, but larger for the Fe, Co, Ni and Cu ions. The binding energies of the transition metal noble gas ions are not accurately predicted at the SCF level, because correlation is required to describe their M(0)Ln(+) character. All trends can be explained in terms of promotion and hybridization on the metal ion.

Magnetic quantization in monolayer bismuthene

NASA Astrophysics Data System (ADS)

Chen, Szu-Chao; Chiu, Chih-Wei; Lin, Hui-Chi; Lin, Ming-Fa

The magnetic quantization in monolayer bismuthene is investigated by the generalized tight-binding model. The quite large Hamiltonian matrix is built from the tight-binding functions of the various sublattices, atomic orbitals and spin states. Due to the strong spin orbital coupling and sp3 bonding, monolayer bismuthene has the diverse low-lying energy bands such as the parabolic, linear and oscillating energy bands. The main features of band structures are further reflected in the rich magnetic quantization. Under a uniform perpendicular magnetic field (Bz) , three groups of Landau levels (LLs) with distinct features are revealed near the Fermi level. Their Bz-dependent energy spectra display the linear, square-root and non-monotonous dependences, respectively. These LLs are dominated by the combinations of the 6pz orbital and (6px,6py) orbitals as a result of strong sp3 bonding. Specifically, the LL anti-crossings only occur between LLs originating from the oscillating energy band.

Interaction of human synovial phospholipase A2 with mixed lipid bilayers: a coarse-grain and all-atom molecular dynamics simulation study.

PubMed

Qin, Shan-Shan; Yu, Yang-Xin; Li, Qi-Kai; Yu, Zhi-Wu

2013-02-26

Human secreted phospholipase A2s have been shown to promote inflammation in mammals by catalyzing the first step of the arachidonic acid pathway by breaking down phospholipids, producing fatty acids, including arachidonic acid. They bind to the membrane water interface to access their phospholipid substrates from the membrane. Their binding modes on membrane surfaces are regulated by diverse factors, including membrane charge, fluidity, and heterogeneity. The influence of these factors on the binding modes of the enzymes is not well understood. Here we have studied several human synovial phospholipase A2 (hs-PLA2)/mixed bilayer systems through a combined coarse-grain and all-atom molecular dynamics simulation. It was found that hydrophobic residues Leu2, Val3, Ala18, Leu19, Phe23, Gly30, and Phe63 that form the edge of the entrance of the hydrophobic binding pocket in hs-PLA2 tend to penetrate into the hydrophobic area of lipid bilayers, and more than half of the total amino acid residues make contact with the lipid headgroups. Each enzyme molecule forms 19-38 hydrogen bonds with the bilayer to which it binds, most of which are with the phosphate groups. Analysis of the root-mean-square deviation (rmsd) shows that residues Val30-Thr40, Tyr66-Gln80, and Lys107-Arg118 have relatively large rmsds during all-atom molecular dynamics simulations, in accordance with the observation of an enlarged entrance region of the hydrophobic binding pocket. The amino acid sequences forming the entrance of the binding pocket prefer to interact with lipid molecules that are more fluid or negatively charged, and the opening of the binding pocket would be larger when the lipid components are more fluid.

Forces and Dynamics of Glucose and Inhibitor Binding to Sodium Glucose Co-transporter SGLT1 Studied by Single Molecule Force Spectroscopy*

PubMed Central

Neundlinger, Isabel; Puntheeranurak, Theeraporn; Wildling, Linda; Rankl, Christian; Wang, Lai-Xi; Gruber, Hermann J.; Kinne, Rolf K. H.; Hinterdorfer, Peter

2014-01-01

Single molecule force spectroscopy was employed to investigate the dynamics of the sodium glucose co-transporter (SGLT1) upon substrate and inhibitor binding on the single molecule level. CHO cells stably expressing rbSGLT1 were probed by using atomic force microscopy tips carrying either thioglucose, 2′-aminoethyl β-d-glucopyranoside, or aminophlorizin. Poly(ethylene glycol) (PEG) chains of different length and varying end groups were used as tether. Experiments were performed at 10, 25 and 37 °C to address different conformational states of SGLT1. Unbinding forces between ligands and SGLT1 were recorded at different loading rates by changing the retraction velocity, yielding binding probability, width of energy barrier of the binding pocket, and the kinetic off rate constant of the binding reaction. With increasing temperature, width of energy barrier and average life time increased for the interaction of SGLT1 with thioglucose (coupled via acrylamide to a long PEG) but decreased for aminophlorizin binding. The former indicates that in the membrane-bound SGLT1 the pathway to sugar translocation involves several steps with different temperature sensitivity. The latter suggests that also the aglucon binding sites for transport inhibitors have specific, temperature-sensitive conformations. PMID:24962566

Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs

NASA Astrophysics Data System (ADS)

Dror, Ron O.; Green, Hillary F.; Valant, Celine; Borhani, David W.; Valcourt, James R.; Pan, Albert C.; Arlow, Daniel H.; Canals, Meritxell; Lane, J. Robert; Rahmani, Raphaël; Baell, Jonathan B.; Sexton, Patrick M.; Christopoulos, Arthur; Shaw, David E.

2013-11-01

The design of G-protein-coupled receptor (GPCR) allosteric modulators, an active area of modern pharmaceutical research, has proved challenging because neither the binding modes nor the molecular mechanisms of such drugs are known. Here we determine binding sites, bound conformations and specific drug-receptor interactions for several allosteric modulators of the M2 muscarinic acetylcholine receptor (M2 receptor), a prototypical family A GPCR, using atomic-level simulations in which the modulators spontaneously associate with the receptor. Despite substantial structural diversity, all modulators form cation-π interactions with clusters of aromatic residues in the receptor extracellular vestibule, approximately 15Å from the classical, `orthosteric' ligand-binding site. We validate the observed modulator binding modes through radioligand binding experiments on receptor mutants designed, on the basis of our simulations, either to increase or to decrease modulator affinity. Simulations also revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites. These observations enabled the design of chemical modifications that substantially alter a modulator's allosteric effects. Our findings thus provide a structural basis for the rational design of allosteric modulators targeting muscarinic and possibly other GPCRs.

Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors

PubMed Central

2016-01-01

Available crystal structures of opioid receptors provide a high-resolution picture of ligand binding at the primary (“orthosteric”) site, that is, the site targeted by endogenous ligands. Recently, positive allosteric modulators of opioid receptors have also been discovered, but their modes of binding and action remain unknown. Here, we use a metadynamics-based strategy to efficiently sample the binding process of a recently discovered positive allosteric modulator of the δ-opioid receptor, BMS-986187, in the presence of the orthosteric agonist SNC-80, and with the receptor embedded in an explicit lipid–water environment. The dynamics of BMS-986187 were enhanced by biasing the potential acting on the ligand–receptor distance and ligand–receptor interaction contacts. Representative lowest-energy structures from the reconstructed free-energy landscape revealed two alternative ligand binding poses at an allosteric site delineated by transmembrane (TM) helices TM1, TM2, and TM7, with some participation of TM6. Mutations of amino acid residues at these proposed allosteric sites were found to either affect the binding of BMS-986187 or its ability to modulate the affinity and/or efficacy of SNC-80. Taken together, these combined experimental and computational studies provide the first atomic-level insight into the modulation of opioid receptor binding and signaling by allosteric modulators. PMID:26841170

Quantum mechanics/molecular mechanics modeling of photoelectron spectra: the carbon 1s core-electron binding energies of ethanol-water solutions.

PubMed

Löytynoja, T; Niskanen, J; Jänkälä, K; Vahtras, O; Rinkevicius, Z; Ågren, H

2014-11-20

Using ethanol-water solutions as illustration, we demonstrate the capability of the hybrid quantum mechanics/molecular mechanics (QM/MM) paradigm to simulate core photoelectron spectroscopy: the binding energies and the chemical shifts. An integrated approach with QM/MM binding energy calculations coupled to preceding molecular dynamics sampling is adopted to generate binding energies averaged over the solute-solvent configurations available at a particular temperature and pressure and thus allowing for a statistical assessment with confidence levels for the final binding energies. The results are analyzed in terms of the contributions in the molecular mechanics model-electrostatic, polarization, and van der Waals-with atom or bond granulation of the corresponding MM charge and polarizability force-fields. The role of extramolecular charge transfer screening of the core-hole and explicit hydrogen bonding is studied by extending the QM core to cover the first solvation shell. The results are compared to those obtained from pure electrostatic and polarizable continuum models. Particularly, the dependence of the carbon 1s binding energies with respect to the ethanol concentration is studied. Our results indicate that QM/MM can be used as an all-encompassing model to study photoelectron binding energies and chemical shifts in solvent environments.

Locating the Binding Sites of Pb(II) Ion with Human and Bovine Serum Albumins

PubMed Central

Belatik, Ahmed; Hotchandani, Surat; Carpentier, Robert; Tajmir-Riahi, Heidar-Ali

2012-01-01

Lead is a potent environmental toxin that has accumulated above its natural level as a result of human activity. Pb cation shows major affinity towards protein complexation and it has been used as modulator of protein-membrane interactions. We located the binding sites of Pb(II) with human serum (HSA) and bovine serum albumins (BSA) at physiological conditions, using constant protein concentration and various Pb contents. FTIR, UV-visible, CD, fluorescence and X-ray photoelectron spectroscopic (XPS) methods were used to analyse Pb binding sites, the binding constant and the effect of metal ion complexation on HSA and BSA stability and conformations. Structural analysis showed that Pb binds strongly to HSA and BSA via hydrophilic contacts with overall binding constants of KPb-HSA = 8.2 (±0.8)×104 M−1 and KPb-BSA = 7.5 (±0.7)×104 M−1. The number of bound Pb cation per protein is 0.7 per HSA and BSA complexes. XPS located the binding sites of Pb cation with protein N and O atoms. Pb complexation alters protein conformation by a major reduction of α-helix from 57% (free HSA) to 48% (metal-complex) and 63% (free BSA) to 52% (metal-complex) inducing a partial protein destabilization. PMID:22574219

DOE Office of Scientific and Technical Information (OSTI.GOV)

Löfling, Jonas; Michael Lyi, Sangbom; Parrish, Colin R.

Feline panleukopenia virus (FPV) is a pathogen whose canine-adapted form (canine parvovirus (CPV)) emerged in 1978. These viruses infect by binding host transferrin receptor type-1 (TfR), but also hemagglutinate erythrocytes. We show that hemagglutination involves selective recognition of the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) but not N-acetylneuraminic acid (Neu5Ac), which differs by only one oxygen atom from Neu5Gc. Overexpression of α2-6 sialyltransferase did not change binding, indicating that both α2-3 and α2-6 linkages are recognized. However, Neu5Gc expression on target cells did not enhance CPV or FPV infection in vitro. Thus, the conserved Neu5Gc-binding preference of these viruses likelymore » plays a role in the natural history of the virus in vivo. Further studies must clarify relationships between virus infection and host Neu5Gc expression. As a first step, we show that transcripts of CMAH (which generates Neu5Gc from Neu5Ac) are at very low levels in Western dog breed cells. - Highlights: ► Feline and canine parvoviruses recognize Neu5Gc but not Neu5Ac, which differ by one oxygen atom. ► The underlying linkage of these sialic acids does not affect recognition. ► Induced Neu5Gc expression on target cells that normally express Neu5Ac did not enhance infection. ► Thus, the conserved binding preference plays an important yet unknown role in in vivo infections. ► Population and breed variations in Neu5Gc expression occur, likely by regulating the gene CMAH.« less

Atomic features of an autoantigen in heparin-induced thrombocytopenia (HIT).

PubMed

Cai, Zheng; Zhu, Zhiqiang; Greene, Mark I; Cines, Douglas B

2016-07-01

Autoantigen development is poorly understood at the atomic level. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by antibodies to an antigen composed of platelet factor 4 (PF4) and heparin or cellular glycosaminoglycans (GAGs). In solution, PF4 exists as an equilibrium among monomers, dimers and tetramers. Structural studies of these interacting components helped delineate a multi-step process involved in the pathogenesis of HIT. First, heparin binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation; exposing the 'open' end. Second, PF4 arrays along heparin/GAG chains, which approximate tetramers, form large antigenic complexes that enhance antibody avidity. Third, pathogenic HIT antibodies bind to the 'open' end of stabilized PF4 tetramers to form an IgG/PF4/heparin ternary immune complex and also to propagate the formation of 'ultralarge immune complexes' (ULCs) that contain multiple IgG antibodies. Fourth, ULCs signal through FcγRIIA receptors, activating platelets and monocytes directly and generating thrombin, which transactivates hematopoietic and endothelial cells. A non-pathogenic anti-PF4 antibody prevents tetramer formation, binding of pathogenic antibody, platelet activation and thrombosis, providing a new approach to manage HIT. An improved understanding of the pathogenesis of HIT may lead to novel diagnostics and therapeutics for this autoimmune disease. Copyright © 2016 Elsevier B.V. All rights reserved.

An investigation of molecular dynamics simulation and molecular docking: interaction of citrus flavonoids and bovine β-lactoglobulin in focus.

PubMed

Sahihi, M; Ghayeb, Y

2014-08-01

Citrus flavonoids are natural compounds with important health benefits. The study of their interaction with a transport protein, such as bovine β-lactoglobulin (BLG), at the atomic level could be a valuable factor to control their transport to biological sites. In the present study, molecular docking and molecular dynamics simulation methods were used to investigate the interaction of hesperetin, naringenin, nobiletin and tangeretin as citrus flavonoids and BLG as transport protein. The molecular docking results revealed that these flavonoids bind in the internal cavity of BLG and the BLG affinity for binding the flavonoids follows naringenin>hesperetin>tangeretin>nobiletin. The docking results also indicated that the BLG-flavonoid complexes are stabilized through hydrophobic interactions, hydrogen bond interactions and π-π stacking interactions. The analysis of molecular dynamics (MD) simulation trajectories showed that the root mean square deviation (RMSD) of various systems reaches equilibrium and fluctuates around the mean value at various times. Time evolution of the radius of gyration, total solvent accessible surface of the protein and the second structure of protein showed as well that BLG and BLG-flavonoid complexes were stable around 2500ps, and there was not any conformational change as for BLG-flavonoid complexes. Further, the profiles of atomic fluctuations indicated the rigidity of the ligand binding site during the simulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Diatomics-in-molecules description of the Rg-Hal2 rare gas-halogen van der Waals complexes with applications to He-Cl2

NASA Astrophysics Data System (ADS)

Grigorenko, B. L.; Nemukhin, A. V.; Buchachenko, A. A.; Stepanov, N. F.; Umanskii, S. Ya.

1997-03-01

The diatomics-in-molecules (DIM) technique is applied for a description of the low-lying states of the Rg-Hal2 van der Waals complexes correlating with the lowest states of constituent atoms Rg(1S)+Hal(2Pj)+Hal(2Pj). The important feature of this approach is the construction of polyatomic basis functions as products of the Hal2 diatomic eigenstates classified within the Hund "c" scheme and the atomic rare gas wave function. Necessary transformations to the other basis set representations are described, and finally all the matrix elements are expressed in terms of nonrelativistic adiabatic energies of Hal2 and Rg Hal fragments and spin-orbit splitting constant of the halogen atom. Our main concern is to test the DIM-based approximations of different levels taking the He-Cl2 system as an example. Namely, we have compared the results obtained within a hierarchy of approaches: (1) the simplest pairwise potential scheme as a far extreme of the DIM model, (2) the same as (1) but with the different components (Σ and Π) for He-Cl interaction, (3) the accurate DIM technique without spin-orbit terms, and (4) the highest level which takes into account all these contributions. The results have been compared to the other DIM like models as well. The shapes of two-dimensional potential surfaces for the ground (X) and excited (B) states of HeCl2, binding energies De with respect to He+Cl2, stretching and bending vibrational frequencies of the complex, binding energies D0, and spectral shifts for the B←X transition are discussed.

A DFT and semiempirical model-based study of opioid receptor affinity and selectivity in a group of molecules with a morphine structural core.

PubMed

Bruna-Larenas, Tamara; Gómez-Jeria, Juan S

2012-01-01

We report the results of a search for model-based relationships between mu, delta, and kappa opioid receptor binding affinity and molecular structure for a group of molecules having in common a morphine structural core. The wave functions and local reactivity indices were obtained at the ZINDO/1 and B3LYP/6-31G(∗∗) levels of theory for comparison. New developments in the expression for the drug-receptor interaction energy expression allowed several local atomic reactivity indices to be included, such as local electronic chemical potential, local hardness, and local electrophilicity. These indices, together with a new proposal for the ordering of the independent variables, were incorporated in the statistical study. We found and discussed several statistically significant relationships for mu, delta, and kappa opioid receptor binding affinity at both levels of theory. Some of the new local reactivity indices incorporated in the theory appear in several equations for the first time in the history of model-based equations. Interaction pharmacophores were generated for mu, delta, and kappa receptors. We discuss possible differences regulating binding and selectivity in opioid receptor subtypes. This study, contrarily to the statistically backed ones, is able to provide a microscopic insight of the mechanisms involved in the binding process.

A molecular mechanism of P-loop pliability of Rho-kinase investigated by molecular dynamic simulation

NASA Astrophysics Data System (ADS)

Gohda, Keigo; Hakoshima, Toshio

2008-11-01

Rho-kinase is a leading player in the regulation of cytoskeletal events involving smooth muscle contraction and neurite growth-cone collapse and retraction, and is a promising drug target in the treatment of both vascular and neurological disorders. Recent crystal structure of Rho-kinase complexed with a small-molecule inhibitor fasudil has revealed structural details of the ATP-binding site, which represents the target site for the inhibitor, and showed that the conserved phenylalanine on the P-loop occupies the pocket, resulting in an increase of protein-ligand contacts. Thus, the P-loop pliability is considered to play an important role in inhibitor binding affinity and specificity. In this study, we carried out a molecular dynamic simulation for Rho-kinase-fasudil complexes with two different P-loop conformations, i.e., the extended and folded conformations, in order to understand the P-loop pliability and dynamics at atomic level. A PKA-fasudil complex was also used for comparison. In the MD simulation, the flip-flop movement of the P-loop conformation starting either from the extended or folded conformation was not able to be observed. However, a significant conformational change in a long loop region covering over the P-loop, and also alteration of ionic interaction-manner of fasudil with acidic residues in the ATP binding site were shown only in the Rho-kinase-fasudil complex with the extended P-loop conformation, while Rho-kinase with the folded P-loop conformation and PKA complexes did not show large fluctuations, suggesting that the Rho-kinase-fasudil complex with the extended P-loop conformation represents a meta-stable state. The information of the P-loop pliability at atomic level obtained in this study could provide valuable clues to designing potent and/or selective inhibitors for Rho-kinase.

Probing the ATP site of GRP78 with nucleotide triphosphate analogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hughes, Scott J.; Antoshchenko, Tetyana; Chen, Yun

GRP78, a member of the ER stress protein family, can relocate to the surface of cancer cells, playing key roles in promoting cell proliferation and metastasis. GRP78 consists of two major functional domains: the ATPase and protein/peptide-binding domains. The protein/peptide-binding domain of cell-surface GRP78 has served as a novel functional receptor for delivering cytotoxic agents (e.g., a apoptosis-inducing peptide or taxol) across the cell membrane. Here, we report our study on the ATPase domain of GRP78 (GRP78 ATPase), whose potential as a transmembrane delivery system of cytotoxic agents (e.g., ATP-based nucleotide triphosphate analogs) remains unexploited. As the binding of ligandsmore » (ATP analogs) to a receptor (GRP78 ATPase) is a pre-requisite for internalization, we determined the binding affinities and modes of GRP78 ATPase for ADP, ATP and several ATP analogs using surface plasmon resonance and x-ray crystallography. The tested ATP analogs contain one of the following modifications: the nitrogen at the adenine ring 7-position to a carbon atom (7-deazaATP), the oxygen at the beta-gamma bridge position to a carbon atom (AMPPCP), or the removal of the 2'-OH group (2'-deoxyATP). We found that 7-deazaATP displays an affinity and a binding mode that resemble those of ATP regardless of magnesium ion (Mg ++) concentration, suggesting that GRP78 is tolerant to modifications at the 7-position. By comparison, AMPPCP's binding affinity was lower than ATP and Mg ++-dependent, as the removal of Mg ++ nearly abolished binding to GRP78 ATPase. The AMPPCP-Mg ++ structure showed evidence for the critical role of Mg ++ in AMPPCP binding affinity, suggesting that while GRP78 is sensitive to modifications at the β-γ bridge position, these can be tolerated in the presence of Mg ++. Furthermore, 2'-deoxyATP's binding affinity was significantly lower than those for all other nucleotides tested, even in the presence of Mg ++. The 2'-deoxyATP structure showed the conformation of the bound nucleotide flipped out of the active site, explaining the low affinity binding to GRP78 and suggesting that the 2'-OH group is essential for the high affinity binding to GRP78. Altogether, our results demonstrate that GRP78 ATPase possesses nucleotide specificity more relaxed than previously anticipated and can tolerate certain modifications to the nucleobase 7-position and, to a lesser extent, the beta-gamma bridging atom, thereby providing a possible atomic mechanism underlying the transmembrane transport of the ATP analogs.« less

Probing the ATP site of GRP78 with nucleotide triphosphate analogs

DOE PAGES

Hughes, Scott J.; Antoshchenko, Tetyana; Chen, Yun; ...

2016-05-04

GRP78, a member of the ER stress protein family, can relocate to the surface of cancer cells, playing key roles in promoting cell proliferation and metastasis. GRP78 consists of two major functional domains: the ATPase and protein/peptide-binding domains. The protein/peptide-binding domain of cell-surface GRP78 has served as a novel functional receptor for delivering cytotoxic agents (e.g., a apoptosis-inducing peptide or taxol) across the cell membrane. Here, we report our study on the ATPase domain of GRP78 (GRP78 ATPase), whose potential as a transmembrane delivery system of cytotoxic agents (e.g., ATP-based nucleotide triphosphate analogs) remains unexploited. As the binding of ligandsmore » (ATP analogs) to a receptor (GRP78 ATPase) is a pre-requisite for internalization, we determined the binding affinities and modes of GRP78 ATPase for ADP, ATP and several ATP analogs using surface plasmon resonance and x-ray crystallography. The tested ATP analogs contain one of the following modifications: the nitrogen at the adenine ring 7-position to a carbon atom (7-deazaATP), the oxygen at the beta-gamma bridge position to a carbon atom (AMPPCP), or the removal of the 2'-OH group (2'-deoxyATP). We found that 7-deazaATP displays an affinity and a binding mode that resemble those of ATP regardless of magnesium ion (Mg ++) concentration, suggesting that GRP78 is tolerant to modifications at the 7-position. By comparison, AMPPCP's binding affinity was lower than ATP and Mg ++-dependent, as the removal of Mg ++ nearly abolished binding to GRP78 ATPase. The AMPPCP-Mg ++ structure showed evidence for the critical role of Mg ++ in AMPPCP binding affinity, suggesting that while GRP78 is sensitive to modifications at the β-γ bridge position, these can be tolerated in the presence of Mg ++. Furthermore, 2'-deoxyATP's binding affinity was significantly lower than those for all other nucleotides tested, even in the presence of Mg ++. The 2'-deoxyATP structure showed the conformation of the bound nucleotide flipped out of the active site, explaining the low affinity binding to GRP78 and suggesting that the 2'-OH group is essential for the high affinity binding to GRP78. Altogether, our results demonstrate that GRP78 ATPase possesses nucleotide specificity more relaxed than previously anticipated and can tolerate certain modifications to the nucleobase 7-position and, to a lesser extent, the beta-gamma bridging atom, thereby providing a possible atomic mechanism underlying the transmembrane transport of the ATP analogs.« less

The stability of vacancy clusters and their effect on helium behaviors in 3C-SiC

NASA Astrophysics Data System (ADS)

Sun, Jingjing; Li, B. S.; You, Yu-Wei; Hou, Jie; Xu, Yichun; Liu, C. S.; Fang, Q. F.; Wang, Z. G.

2018-05-01

We have carried out systematical ab initio calculations to study the stability of vacancy clusters and their effect on helium behaviors in 3C-SiC. It is found that the formation energies of vacancy clusters containing only carbon vacancies are the lowest although the vacancies are not closest to each other, while the binding energies of vacancy clusters composed of both silicon and carbon vacancies in the closest neighbors to each other are the highest. Vacancy clusters can provide with free space for helium atoms to aggregate, while interstitial sites are not favorable for helium atoms to accumulate. The binding energies of vacancy clusters with helium atoms increase almost linearly with the ratio of helium to vacancy, n/m. The binding strength of vacancy cluster having the participation of the silicon vacancy with helium is relatively stronger than that without silicon vacancy. The vacancy clusters with more vacancies can trap helium atoms more tightly. With the presence of vacancy clusters in the material, the diffusivity of helium will be significantly reduced. Moreover, the three-dimension electron density is calculated to analyze the interplay of vacancy clusters with helium.

Investigation on the neutral and anionic BxAlyH2 (x + y = 7, 8, 9) clusters using density functional theory combined with photoelectron spectroscopy.

PubMed

Ding, Li-Ping; Shao, Peng; Lu, Cheng; Zhang, Fang-Hui; Ding, Lei; Yuan, Tao Li

2016-08-17

The structure and bonding nature of neutral and negatively charged BxAlyH2 (x + y = 7, 8, 9) clusters are investigated with the aid of previously published experimental photoelectron spectra combined with the present density functional theory calculations. The comparison between the experimental photoelectron spectra and theoretical simulated spectra helps to identify the ground state structures. The accuracy of the obtained ground state structures is further verified by calculating their adiabatic electron affinities and vertical detachment energies and comparing them against available experimental data. The results show that the structures of BxAlyH2 transform from three-dimensional to planar structures as the number of boron atoms increases. Moreover, boron atoms tend to bind together forming Bn units. The hydrogen atoms prefer to bind with boron atoms rather than aluminum atoms. The analyses of the molecular orbital on the ground state structures further support the abovementioned results.

Free-energy landscape of intrinsically disordered proteins investigated by all-atom multicanonical molecular dynamics.

PubMed

Higo, Junichi; Umezawa, Koji

2014-01-01

We introduce computational studies on intrinsically disordered proteins (IDPs). Especially, we present our multicanonical molecular dynamics (McMD) simulations of two IDP-partner systems: NRSF-mSin3 and pKID-KIX. McMD is one of enhanced conformational sampling methods useful for conformational sampling of biomolecular systems. IDP adopts a specific tertiary structure upon binding to its partner molecule, although it is unstructured in the unbound state (i.e. the free state). This IDP-specific property is called "coupled folding and binding". The McMD simulation treats the biomolecules with an all-atom model immersed in an explicit solvent. In the initial configuration of simulation, IDP and its partner molecules are set to be distant from each other, and the IDP conformation is disordered. The computationally obtained free-energy landscape for coupled folding and binding has shown that native- and non-native-complex clusters distribute complicatedly in the conformational space. The all-atom simulation suggests that both of induced-folding and population-selection are coupled complicatedly in the coupled folding and binding. Further analyses have exemplified that the conformational fluctuations (dynamical flexibility) in the bound and unbound states are essentially important to characterize IDP functioning.

Non-local electron transport through normal and topological ladder-like atomic systems

NASA Astrophysics Data System (ADS)

Kurzyna, Marcin; Kwapiński, Tomasz

2018-05-01

We propose a locally protected ladder-like atomic system (nanoconductor) on a substrate that is insensitive to external perturbations. The system corresponds to coupled atomic chains fabricated on different surfaces. Electron transport properties of such conductors are studied theoretically using the model tight-binding Su-Schriffer-Hegger (SSH) Hamiltonian and Green's function formalism. We have found that the conductance of the system is almost insensitive to single adatoms and oscillates as a function of the side chain length with very large periods. Non-local character of the electron transport was observed also for topological SSH chains where nontrivial end states survive in the presence of disturbances as well as for different substrates. We have found that the careful inspection of the density of states or charge waves can provide the information about the atom energy levels and hopping amplitudes. Moreover, the ladder-like geometry allows one to distinguish between normal and topological zero-energy states. It is important that topological chains do not reveal Friedel oscillations which are observed in non-topological chains.

Atomistic simulation of the trapping capability of He-vacancy defects at Ni {\\sum}^{}3\\left(1\\bar{1}2\\right)[110] grain boundary

NASA Astrophysics Data System (ADS)

Gong, Hengfeng; Wang, Chengbin; Zhang, Wei; Huai, Ping; Lu, Wei; Zhu, Zhiyuan

2016-12-01

He atoms tend to cluster and precipitate into bubbles that prefer to grow in the grain boundaries, resulting in high temperature He embrittlement with significantly degraded material properties. This is a major bottleneck in employing Ni-based alloys for applications such as molten salt reactors (MSRs). This paper focuses on understanding how the local grain boundary structure interacts with He atoms and how the local atomistic environment in the grain boundary influences the binding energy of He defects. Using molecular dynamics simulations, we have investigated the trapping capability of the Ni {\\sum}3≤ft(1 \\bar{1} 2\\right)≤ft[1 1 0\\right] grain boundary to He defects (He N ) and to He-vacancy defects (He N V M ). The two defects in the Ni grain boundary exhibit geometries with high symmetry. The binding energy of an interstitial He atom to He N V M defects is found to be generally larger in pure Ni than that in the grain boundary. We compared the binding energy of He N defects to the Ni vacancy and to the Ni grain boundary, finding that the Ni vacancy possesses a higher trapping strength to He N . We also found that the binding strength of He N to the grain boundary is stronger than that of He N V M to the grain boundary. The He-vacancy ratio in He N V M defects does not significantly affect the binding energy in the grain boundary plane. The current work will provide insight in understanding the experimentally observed He bubble formation in Ni-based alloys and bridge atomic scale events and damage with macroscopic failure.

Simple method for determining binding energies of fullerene and complex atomic negative ions

NASA Astrophysics Data System (ADS)

Felfli, Zineb; Msezane, Alfred

2017-04-01

A robust potential which embeds fully the vital core polarization interaction has been used in the Regge pole method to explore low-energy electron scattering from C60, Eu and Nb through the total cross sections (TCSs) calculations. From the characteristic dramatically sharp resonances in the TCSs manifesting negative ion formation in these systems, we extracted the binding energies for the C60, Euand Nbanions they are found to be in outstanding agreement with the measured electron affinities of C60, Eu and Nb. Common among these considered systems, including the standard atomic Au is the formation of their ground state negative ions at the second Ramsauer-Townsend (R-T) minima of their TCSs. Indeed, this is a signature of all the fullerenes and complex atoms considered thus far. Shape resonances, R-T minima and binding energies of the resultant anions are presented. This work was supported by U.S. DOE, Basic Energy Sciences, Office of Energy Research.

Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations.

PubMed

Yu, Zhe; Ma, Yu-chi; Ai, Jing; Chen, Dan-qi; Zhao, Dong-mei; Wang, Xin; Chen, Yue-lei; Geng, Mei-yu; Xiong, Bing; Cheng, Mao-sheng; Shen, Jing-Kang

2013-11-01

To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors. Based on the prototype model inhibitor 1, four ligands with subtle differences in the fused aromatic rings were synthesized. Quantum chemistry was employed to calculate the binding free energy for each ligand. Symmetry-adapted perturbation theory (SAPT) was used to decompose the binding energy into several fundamental forces to elucidate the determinant factors. Binding free energies calculated from quantum chemistry were correlated well with experimental data. SAPT calculations showed that the predominant driving force for binding was derived from a sandwich π-π interaction with Tyr-1230. Arg-1208 was the differentiating factor, interacting with the 6-position of the fused aromatic ring system through the backbone carbonyl with a force pattern similar to hydrogen bonding. Therefore, a hydrogen atom must be attached at the 6-position, and changing the carbon atom to nitrogen caused unfavorable electrostatic interactions. The theoretical studies have elucidated the determinant factors involved in the binding of type I inhibitors to c-Met.

Pursuit of the Kramers-Henneberger atom

NASA Astrophysics Data System (ADS)

Wei, Qi; Wang, Pingxiao; Kais, Sabre; Herschbach, Dudley

2017-09-01

Superstrong femtosecond pulsed lasers can profoundly alter electronic structure of atoms and molecules. The oscillating laser field drives one or more electrons almost free. When averaged over, the rapid oscillations combine with the static Coulomb potential to create an effective binding potential. The consequent array of bound states comprises the ;Kramers-Henneberger Atom;. Theorists have brought forth many properties of KH atoms, yet convincing experimental evidence is meager. We examine a remarkable experiment accelerating atoms (Eichmann et al., 2009). It offers tantalizing evidence for the KH atom, with prospects for firm confirmation by adjustment of laser parameters.

Cavity Versus Ligand Shape Descriptors: Application to Urokinase Binding Pockets.

PubMed

Cerisier, Natacha; Regad, Leslie; Triki, Dhoha; Camproux, Anne-Claude; Petitjean, Michel

2017-11-01

We analyzed 78 binding pockets of the human urokinase plasminogen activator (uPA) catalytic domain extracted from a data set of crystallized uPA-ligand complexes. These binding pockets were computed with an original geometric method that does NOT involve any arbitrary parameter, such as cutoff distances, angles, and so on. We measured the deviation from convexity of each pocket shape with the pocket convexity index (PCI). We defined a new pocket descriptor called distributional sphericity coefficient (DISC), which indicates to which extent the protein atoms of a given pocket lie on the surface of a sphere. The DISC values were computed with the freeware PCI. The pocket descriptors and their high correspondences with ligand descriptors are crucial for polypharmacology prediction. We found that the protein heavy atoms lining the urokinases binding pockets are either located on the surface of their convex hull or lie close to this surface. We also found that the radii of the urokinases binding pockets and the radii of their ligands are highly correlated (r = 0.9).

Magnetic resonance studies of atomic hydrogen at zero field and low temperature: Recombination and binding on liquid helium

NASA Astrophysics Data System (ADS)

Jochemsen, R.; Morrow, M.; Berlinsky, A. J.; Hardy, W. N.

1982-07-01

Magnetic resonance studies at zero field are reported for atomic hydrogen gas confined in a closed glass bulb with helium-coated walls for T < 1 K in a dilution refrigerator. Low-energy r.f. discharge pulses have been used to produce H atoms at temperatures as low as T = 0.06 K. The atom density nH (10 9 < nH < 10 13) measured by the strength of the free induction decay signal, follows a second-order rate equation {dn H}/{dt} = -Kn H2. At the lowest temperatures recombination is dominated by the process H + H+ wall → H 2 + wall. From the temperature dependence of the rate constant K we have determined the binding energy of H on liquid 4He and 3He, and also the cross section for recombination on the surface.

Atomically precise organomimetic cluster nanomolecules assembled via perfluoroaryl-thiol SNAr chemistry

NASA Astrophysics Data System (ADS)

Qian, Elaine A.; Wixtrom, Alex I.; Axtell, Jonathan C.; Saebi, Azin; Jung, Dahee; Rehak, Pavel; Han, Yanxiao; Moully, Elamar Hakim; Mosallaei, Daniel; Chow, Sylvia; Messina, Marco S.; Wang, Jing Yang; Royappa, A. Timothy; Rheingold, Arnold L.; Maynard, Heather D.; Král, Petr; Spokoyny, Alexander M.

2017-04-01

The majority of biomolecules are intrinsically atomically precise, an important characteristic that enables rational engineering of their recognition and binding properties. However, imparting a similar precision to hybrid nanoparticles has been challenging because of the inherent limitations of existing chemical methods and building blocks. Here we report a new approach to form atomically precise and highly tunable hybrid nanomolecules with well-defined three-dimensionality. Perfunctionalization of atomically precise clusters with pentafluoroaryl-terminated linkers produces size-tunable rigid cluster nanomolecules. These species are amenable to facile modification with a variety of thiol-containing molecules and macromolecules. Assembly proceeds at room temperature within hours under mild conditions, and the resulting nanomolecules exhibit high stabilities because of their full covalency. We further demonstrate how these nanomolecules grafted with saccharides can exhibit dramatically improved binding affinity towards a protein. Ultimately, the developed strategy allows the rapid generation of precise molecular assemblies to investigate multivalent interactions.

Presynaptic Filament Dynamics in Homologous Recombination and DNA Repair

PubMed Central

Liu, Jie; Ehmsen, Kirk T.; Heyer, Wolf-Dietrich; Morrical, Scott W.

2014-01-01

Homologous Recombination (HR) is an essential genome stability mechanism used for high-fidelity repair of DNA double-strand breaks and for the recovery of stalled or collapsed DNA replication forks. The crucial homology search and DNA strand exchange steps of HR are catalyzed by presynaptic filaments—helical filaments of a recombinase enzyme bound to single-stranded DNA. Presynaptic filaments are fundamentally dynamic structures, the assembly, catalytic turnover, and disassembly of which must be closely coordinated with other elements of the DNA recombination, repair, and replication machinery in order for genome maintenance functions to be effective. Here, we review the major dynamic elements controlling the assembly, activity, and disassembly of presynaptic filaments: some intrinsic such as recombinase ATP binding and hydrolytic activities, others extrinsic such as ssDNA-binding proteins, mediator proteins, and DNA motor proteins. We examine dynamic behavior on multiple levels, including atomic- and filament-level structural changes associated with ATP binding and hydrolysis as evidenced in crystal structures, as well as subunit binding and dissociation events driven by intrinsic and extrinsic factors. We examine the biochemical properties of recombination proteins from four model systems (T4 phage, E. coli, S. cerevisiae, and H. sapiens), demonstrating how their properties are tailored for the context-specific requirements in these diverse species. We propose that the presynaptic filament has evolved to rely on multiple external factors for increased multi-level regulation of HR processes in genomes with greater structural and sequence complexity. PMID:21599536

Molecular dynamics simulation of the interactions between EHD1 EH domain and multiple peptides.

PubMed

Yu, Hua; Wang, Mao-jun; Xuan, Nan-xia; Shang, Zhi-cai; Wu, Jun

2015-10-01

To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 (EHD1 EH domain) with three peptides containing NPF (asparagine-proline-phenylalanine), DPF (aspartic acid-proline-phenylalanine), and GPF (glycine-proline-phenylalanine) motifs were deciphered at the atomic level. The binding affinities and the underlying structure basis were investigated. Molecular dynamics (MD) simulations were performed on EHD1 EH domain/peptide complexes for 60 ns using the GROMACS package. The binding free energies were calculated and decomposed by molecular mechanics/generalized Born surface area (MM/GBSA) method using the AMBER package. The alanine scanning was performed to evaluate the binding hot spot residues using FoldX software. The different binding affinities for the three peptides were affected dominantly by van der Waals interactions. Intermolecular hydrogen bonds provide the structural basis of contributions of van der Waals interactions of the flanking residues to the binding. van der Waals interactions should be the main consideration when we design peptide inhibitors of EHD1 EH domain with high affinities. The ability to form intermolecular hydrogen bonds with protein residues can be used as the factor for choosing the flanking residues.

A molecular model for cocaine binding by the immunotherapeutic human/mouse chimeric monoclonal antibody 2E2.

PubMed

Lape, Michael; Paula, Stefan; Ball, William J

2010-06-01

Immunotherapy by cocaine-binding monoclonal antibodies (mAbs) has emerged as a promising strategy for the treatment of cocaine addiction. The human (gamma1 heavy chain)/murine (lambda light chain) chimeric mAb 2E2 has excellent affinity and specificity for cocaine and recent animal studies have demonstrated 2E2's ability in vivo to reduce cocaine levels in the brain as well as alter cocaine self-administration behavior in rats. In this study, we used mAb 2E2 amino acid sequence information to create a homology model for the 3-D structure of its Fv fragment. Subsequent computational docking studies revealed the intermolecular interactions potentially responsible for mAb 2E2's cocaine binding properties. The driving force of cocaine binding was identified as a combination of hydrophobic interactions and a single hydrogen bond between a light chain tyrosine residue and a carbonyl oxygen atom of cocaine. The model also allowed for an in silico evaluation of single/double residue mutations in the heavy and light chain variable regions that might further enhance mAb 2E2's cocaine binding properties. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

A Molecular Model for Cocaine Binding by the Immunotherapeutic Human/Mouse Chimeric Monoclonal Antibody 2E2

PubMed Central

Lape, Michael; Paula, Stefan; Ball, William J.

2010-01-01

Immunotherapy by cocaine-binding monoclonal antibodies (mAbs) has emerged as a promising strategy for the treatment of cocaine addiction. The human (γ1 heavy chain)/murine (λ light chain) chimeric mAb 2E2 has excellent affinity and specificity for cocaine and recent animal studies have demonstrated 2E2’s ability in vivo to reduce cocaine levels in the brain as well as alter cocaine self-administration behavior in rats. In this study, we used mAb 2E2 amino acid sequence information to create a homology model for the 3-D structure of its Fv fragment. Subsequent computational docking studies revealed the intermolecular interactions potentially responsible for mAb 2E2’s cocaine binding properties. The driving force of cocaine binding was identified as a combination of hydrophobic interactions and a single hydrogen bond between a light chain tyrosine residue and a carbonyl oxygen atom of cocaine. The model also allowed for an in silico evaluation of single/double residue mutations in the heavy and light chain variable regions that might further enhance mAb 2E2’s cocaine binding properties. PMID:20185210

Dark Matter Detection Using Helium Evaporation and Field Ionization

NASA Astrophysics Data System (ADS)

Maris, Humphrey J.; Seidel, George M.; Stein, Derek

2017-11-01

We describe a method for dark matter detection based on the evaporation of helium atoms from a cold surface and their subsequent detection using field ionization. When a dark matter particle scatters off a nucleus of the target material, elementary excitations (phonons or rotons) are produced. Excitations which have an energy greater than the binding energy of helium to the surface can result in the evaporation of helium atoms. We propose to detect these atoms by ionizing them in a strong electric field. Because the binding energy of helium to surfaces can be below 1 meV, this detection scheme opens up new possibilities for the detection of dark matter particles in a mass range down to 1 MeV /c2 .

Dark Matter Detection Using Helium Evaporation and Field Ionization.

PubMed

Maris, Humphrey J; Seidel, George M; Stein, Derek

2017-11-03

We describe a method for dark matter detection based on the evaporation of helium atoms from a cold surface and their subsequent detection using field ionization. When a dark matter particle scatters off a nucleus of the target material, elementary excitations (phonons or rotons) are produced. Excitations which have an energy greater than the binding energy of helium to the surface can result in the evaporation of helium atoms. We propose to detect these atoms by ionizing them in a strong electric field. Because the binding energy of helium to surfaces can be below 1 meV, this detection scheme opens up new possibilities for the detection of dark matter particles in a mass range down to 1  MeV/c^{2}.

Atomic and molecular adsorption on Au(111)

DOE PAGES

Santiago-Rodriguez, Yohaselly; Herron, Jeffrey A.; Curet-Arana, Maria C.; ...

2014-05-02

Periodic self-consistent density functional theory (DFT-GGA) calculations were used to study the adsorption of several atomic species, molecular species and molecular fragments on the Au(111) surface with a coverage of 1/4 monolayer (ML). Binding geometries, binding energies, and diffusion barriers were calculated for 27 species. Furthermore, we calculated the surface deformation energy associated with the binding events. The binding strength for all the analyzed species can be ordered as follows: NH 3 < NO < CO < CH 3 < HCO < NH 2 < COOH < OH < HCOO < CNH 2 < H < N < NH

Theoretical realization of cluster-assembled hydrogen storage materials based on terminated carbon atomic chains.

PubMed

Liu, Chun-Sheng; An, Hui; Guo, Ling-Ju; Zeng, Zhi; Ju, Xin

2011-01-14

The capacity of carbon atomic chains with different terminations for hydrogen storage is studied using first-principles density functional theory calculations. Unlike the physisorption of H(2) on the H-terminated chain, we show that two Li (Na) atoms each capping one end of the odd- or even-numbered carbon chain can hold ten H(2) molecules with optimal binding energies for room temperature storage. The hybridization of the Li 2p states with the H(2)σ orbitals contributes to the H(2) adsorption. However, the binding mechanism of the H(2) molecules on Na arises only from the polarization interaction between the charged Na atom and the H(2). Interestingly, additional H(2) molecules can be bound to the carbon atoms at the chain ends due to the charge transfer between Li 2s2p (Na 3s) and C 2p states. More importantly, dimerization of these isolated metal-capped chains does not affect the hydrogen binding energy significantly. In addition, a single chain can be stabilized effectively by the C(60) fullerenes termination. With a hydrogen uptake of ∼10 wt.% on Li-coated C(60)-C(n)-C(60) (n = 5, 8), the Li(12)C(60)-C(n)-Li(12)C(60) complex, keeping the number of adsorbed H(2) molecules per Li and stabilizing the dispersion of individual Li atoms, can serve as better building blocks of polymers than the (Li(12)C(60))(2) dimer. These findings suggest a new route to design cluster-assembled hydrogen storage materials based on terminated sp carbon chains.

Formic acid decomposition on Pt1/Cu (111) single platinum atom catalyst: Insights from DFT calculations and energetic span model analysis

NASA Astrophysics Data System (ADS)

Wang, Ying-Fan; Li, Kun; Wang, Gui-Chang

2018-04-01

Inspired by the recent surface experimental results that the monatomic Pt catalysts has more excellent hydrogen production that Cu(111) surface, the mechanism of decomposition of formic acid on Cu(111) and single atom Pt1/Cu(111) surface was studied by periodic density functional theory calculations in the present work. The results show that the formic acid tends to undergo dehydrogenation on both surfaces to obtain the hydrogen product of the target product, and the selectivity and catalytic activity of Pt1/Cu (111) surface for formic acid dehydrogenation are better. The reason is that the single atom Pt1/Cu(111) catalyst reduces the reaction energy barrier (i.e., HCOO → CO2 + H) of the critical step of the dehydrogenation reaction due to the fact that the single atom Pt1/Cu(111) catalyst binds formate weakly compared to that of Cu (111) one. Moreover, it was found that the Pt1/Cu (111) binds CO more strongly than that of Cu (111) one and thus leading to the difficult for the formation of CO. These two factors would make the single Pt atom catalyst had the high selectivity for the H2 production. It is hoped that the present work may help people to design the efficient H2 production from HCOOH decomposition by reduce the surface binding strength of HCOO species, for example, using the low coordination number active site like single atom or other related catalytic system.

Magnetic properties of Mg12O12 nanocage doped with transition metal atoms (Mn, Fe, Co and Ni): DFT study

NASA Astrophysics Data System (ADS)

Javan, Masoud Bezi

2015-07-01

Binding energy of the Mg12O12 nanocage doped with transition metals (TM=Mn, Fe, Co and Ni) in endohedrally, exohedrally and substitutionally forms were studied using density functional theory with the generalized gradient approximation exchange-correlation functional along 6 different paths inside and outside of the Mg12O12 nanocage. The most stable structures were determined with full geometry optimization near the minimum of the binding energy curves of all the examined paths inside and outside of the Mg12O12 nanocage. The results reveal that for all stable structures, the Ni atom has a larger binding energy than the other TM atoms. It is also found that for all complexes additional peaks contributed by TM-3d, 4s and 4p states appear in the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) gap of the host MgO cluster. The mid-gap states are mainly due to the hybridization between TM-3d, 4s and 4p orbitals and the cage π orbitals. The magnetic moment of the endohedrally doped TM atoms in the Mg12O12 are preserved to some extent due to the interaction between the TM and Mg12O12 nanocage, in contrast to the completely quenched magnetic moment of the Fe and Ni atoms in the Mg11(TM)O12 complexes. Furthermore, charge population analysis shows that charge transfer occurs from TM atom to the cage for endohedrally and substitutionally doping.

Mannobiose Binding Induces Changes in Hydrogen Bonding and Protonation States of Acidic Residues in Concanavalin A As Revealed by Neutron Crystallography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerlits, Oksana O.; Coates, Leighton; Woods, Robert J.

Plant lectins are carbohydrate-binding proteins with various biomedical applications. Concanavalin A (Con A) holds promise in treating cancerous tumors. To better understand the Con A carbohydrate binding specificity, we obtained a room-temperature neutron structure of this legume lectin in complex with a disaccharide Manα1–2Man, mannobiose. The neutron structure afforded direct visualization of the hydrogen bonding between the protein and ligand, showing that the ligand is able to alter both protonation states and interactions for residues located close to and distant from the binding site. An unprecedented low-barrier hydrogen bond was observed forming between the carboxylic side chains of Asp28 andmore » Glu8, with the D atom positioned equidistant from the oxygen atoms having an O···D···O angle of 101.5°.« less

Acceptor binding energies in GaN and AlN

NASA Astrophysics Data System (ADS)

Mireles, Francisco; Ulloa, Sergio E.

1998-08-01

We employ effective-mass theory for degenerate hole bands to calculate the acceptor binding energies for Be, Mg, Zn, Ca, C, and Si substitutional acceptors in GaN and AlN. The calculations are performed through the 6×6 Rashba-Sheka-Pikus and the Luttinger-Kohn matrix Hamiltonians for wurtzite (WZ) and zinc-blende (ZB) crystal phases, respectively. An analytic representation for the acceptor pseudopotential is used to introduce the specific nature of the impurity atoms. The energy shift due to polaron effects is also considered in this approach. The ionization energy estimates are in very good agreement with those reported experimentally in WZ GaN. The binding energies for ZB GaN acceptors are all predicted to be shallower than the corresponding impurities in the WZ phase. The binding-energy dependence upon the crystal-field splitting in WZ GaN is analyzed. Ionization levels in AlN are found to have similar ``shallow'' values to those in GaN, but with some important differences which depend on the band structure parametrizations, especially the value of the crystal-field splitting used.

Computational study of the binding of CuII to Alzheimer's amyloid-beta peptide: do Abeta42 and Abeta40 bind copper in identical fashion?

PubMed

Mantri, Yogita; Fioroni, Marco; Baik, Mu-Hyun

2008-11-01

One of the many hypotheses on the pathogenesis of Alzheimer's disease is that the amyloid-beta peptide (Abeta) binds CuII and can catalytically generate H2O2, leading to oxidative damage in brain tissues. For a molecular level understanding of such catalysis it is critical to know the structure of the Abeta-CuII complex precisely. Unfortunately, no high-resolution structure is available to date and there is considerable debate over the copper coordination environment with no clear consensus on which residues are directly bound to CuII. Considering all plausible isomers of the copper-bound Abeta42 and Abeta40 using a combination of density functional theory and classical molecular dynamics methods, we report an atomic resolution structure for each possible complex. We evaluated the relative energies of these isomeric structures and surprisingly found that Abeta42 and Abeta40 display very different binding modes, suggesting that shorter peptides that are truncated at the C-terminus may not be realistic models for understanding the chemistry of the most neurotoxic peptide, Abeta42.

Mechanistic events underlying odorant binding protein chemoreception.

PubMed

Golebiowski, Jérôme; Antonczak, Serge; Fiorucci, Sébastien; Cabrol-Bass, Daniel

2007-05-01

Odorant binding proteins (OBP's) are small hydrophilic proteins, belonging to the lipocalin family dedicated to bind and transport small hydrophobic ligands. Despite many works, the mechanism of ligand binding, together with the functional role of these proteins remains a topic of debate and little is known at the atomic level. The present work reports a computational study of odorants capture and release by an OBP, using both constrained and unconstrained simulations, giving a glimpse on the molecular mechanism of chemoreception. The residues at the origin of the regulation of the protein door opening are identified and a tyrosine amino-acid together with other nearby residues appear to play a crucial role in allowing this event to occur. The simulations reveal that this tyrosine and the protein's L5 loop are implicated in the ligand contact with the protein and act as an anchoring point for the ligand. The protein structural features required for the ligand entry are highly conserved among many transport proteins, suggesting that this mechanism could somewhat be extended to some members of the larger family of lipocalin. (c) 2007 Wiley-Liss, Inc.

Modes of action for arsenic carcinogenesis and toxicity

EPA Science Inventory

There are three principal ways in which arsenic species can interact with important biological molecules. First, trivalent arsenicals can bind to macromolecule sites, principally the sulfhydryls of peptides and proteins. Selenocysteines, selenium atoms and molybdenum atoms are al...

Reference binding energies of transition metal carbides by core-level x-ray photoelectron spectroscopy free from Ar+ etching artefacts

NASA Astrophysics Data System (ADS)

Greczynski, G.; Primetzhofer, D.; Hultman, L.

2018-04-01

We report x-ray photoelectron spectroscopy (XPS) core level binding energies (BE's) for the widely-applicable groups IVb-VIb transition metal carbides (TMCs) TiC, VC, CrC, ZrC, NbC, MoC, HfC, TaC, and WC. Thin film samples are grown in the same deposition system, by dc magnetron co-sputtering from graphite and respective elemental metal targets in Ar atmosphere. To remove surface contaminations resulting from exposure to air during sample transfer from the growth chamber into the XPS system, layers are either (i) Ar+ ion-etched or (ii) UHV-annealed in situ prior to XPS analyses. High resolution XPS spectra reveal that even gentle etching affects the shape of core level signals, as well as BE values, which are systematically offset by 0.2-0.5 eV towards lower BE. These destructive effects of Ar+ ion etch become more pronounced with increasing the metal atom mass due to an increasing carbon-to-metal sputter yield ratio. Systematic analysis reveals that for each row in the periodic table (3d, 4d, and 5d) C 1s BE increases from left to right indicative of a decreased charge transfer from TM to C atoms, hence bond weakening. Moreover, C 1s BE decreases linearly with increasing carbide/metal melting point ratio. Spectra reported here, acquired from a consistent set of samples in the same instrument, should serve as a reference for true deconvolution of complex XPS cases, including multinary carbides, nitrides, and carbonitrides.

Variational calculation of ground-state energy of iron atoms and condensed matter in strong magnetic fields. [at neutron star surfaces

NASA Technical Reports Server (NTRS)

Flowers, E. G.; Ruderman, M. A.; Lee, J.-F.; Sutherland, P. G.; Hillebrandt, W.; Mueller, E.

1977-01-01

Variational calculations of the binding energies of iron atoms and condensed matter in strong magnetic fields (greater than 10 to the 12th gauss). These calculations include the electron exchange energy. The cohesive energy of the condensed matter, which is the difference between these two binding energies, is of interest in pulsar theories and in the description of the surfaces of neutron stars. It is found that the cohesive energy ranges from 2.6 keV to 8.0 keV.

Computational study on the interactions and orientation of monoclonal human immunoglobulin G on a polystyrene surface

PubMed Central

Javkhlantugs, Namsrai; Bayar, Hexig; Ganzorig, Chimed; Ueda, Kazuyoshi

2013-01-01

Having a theoretical understanding of the orientation of immunoglobulin on an immobilized solid surface is important in biomedical pathogen-detecting systems and cellular analysis. Despite the stable adsorption of immunoglobulin on a polystyrene (PS) surface that has been applied in many kinds of immunoassays, there are many uncertainties in antibody-based clinical and biological experimental methods. To understand the binding mechanism and physicochemical interactions between immunoglobulin and the PS surface at the atomic level, we investigated the binding behavior and interactions of the monoclonal immunoglobulin G (IgG) on the PS surface using the computational method. In our docking simulation with the different arrangement of translational and rotational orientation of IgG onto the PS surface, three typical orientation patterns of the immunoglobulin G on the PS surface were found. We precisely analyzed these orientation patterns and clarified how the immunoglobulin G interacts with the PS surface at atomic scale in the beginning of the adsorption process. Major driving forces for the adsorption of IgG onto the PS surface come from serine (Ser), aspartic acid (Asp), and glutamic acid (Glu) residues. PMID:23874096

Pseudopotentials for quantum Monte Carlo studies of transition metal oxides

DOE PAGES

Krogel, Jaron T.; Santana Palacio, Juan A.; Reboredo, Fernando A.

2016-02-22

Quantum Monte Carlo (QMC) calculations of transition metal oxides are partially limited by the availability of high-quality pseudopotentials that are both accurate in QMC and compatible with major plane-wave electronic structure codes. We have generated a set of neon-core pseudopotentials with small cutoff radii for the early transition metal elements Sc to Zn within the local density approximation of density functional theory. The pseudopotentials have been directly tested for accuracy within QMC by calculating the first through fourth ionization potentials of the isolated transition metal (M) atoms and the binding curve of each M-O dimer. We find the ionization potentialsmore » to be accurate to 0.16(1) eV, on average, relative to experiment. The equilibrium bond lengths of the dimers are within 0.5(1)% of experimental values, on average, and the binding energies are also typically accurate to 0.18(3) eV. The level of accuracy we find for atoms and dimers is comparable to what has recently been observed for bulk metals and oxides using the same pseudopotentials. Our QMC pseudopotential results compare well with the findings of previous QMC studies and benchmark quantum chemical calculations.« less

An ab initio study on MgX 3- and CaX 3- superhalogen anions (X=F, Cl, Br)

NASA Astrophysics Data System (ADS)

Anusiewicz, Iwona; Sobczyk, Monika; Dąbkowska, Iwona; Skurski, Piotr

2003-06-01

The vertical electron detachment energies (VDEs) of twenty MX 3- (M=Mg, Ca; X=F, Cl, Br) anions were calculated at the OVGF level with the 6-311++G(3df) basis sets. The largest vertical electron binding energy was found for MgF 3- system (8.793 eV). All negatively charged species possess the VDEs that are larger than 5.9 eV and thus may be termed superhalogen anions. The strong dependence of the VDE of the MX 3- species on the ligand-central atom (M-X) distance and on the partial atomic charge localized on Mg or Ca was observed and discussed, as well as the other factors that may influence the electronic stability of such anions.

Regulation of the protein-conducting channel by a bound ribosome

PubMed Central

Gumbart, James; Trabuco, Leonardo G.; Schreiner, Eduard; Villa, Elizabeth; Schulten, Klaus

2009-01-01

Summary During protein synthesis, it is often necessary for the ribosome to form a complex with a membrane-bound channel, the SecY/Sec61 complex, in order to translocate nascent proteins across a cellular membrane. Structural data on the ribosome-channel complex are currently limited to low-resolution cryo-electron microscopy maps, including one showing a bacterial ribosome bound to a monomeric SecY complex. Using that map along with available atomic-level models of the ribosome and SecY, we have determined, through molecular dynamics flexible fitting (MDFF), an atomic-resolution model of the ribosome-channel complex. We characterized computationally the sites of ribosome-SecY interaction within the complex and determined the effect of ribosome binding on the SecY channel. We also constructed a model of a ribosome in complex with a SecY dimer by adding a second copy of SecY to the MDFF-derived model. The study involved 2.7-million-atom simulations over altogether nearly 50 ns. PMID:19913480

A Highly Expressed High-Molecular-Weight S-Layer Complex of Pelosinus sp. Strain UFO1 Binds Uranium

PubMed Central

Thorgersen, Michael P.; Lancaster, W. Andrew; Rajeev, Lara; Ge, Xiaoxuan; Vaccaro, Brian J.; Poole, Farris L.; Arkin, Adam P.; Mukhopadhyay, Aindrila

2016-01-01

ABSTRACT Cell suspensions of Pelosinus sp. strain UFO1 were previously shown, using spectroscopic analysis, to sequester uranium as U(IV) complexed with carboxyl and phosphoryl group ligands on proteins. The goal of our present study was to characterize the proteins involved in uranium binding. Virtually all of the uranium in UFO1 cells was associated with a heterodimeric protein, which was termed the uranium-binding complex (UBC). The UBC was composed of two S-layer domain proteins encoded by UFO1_4202 and UFO1_4203. Samples of UBC purified from the membrane fraction contained 3.3 U atoms/heterodimer, but significant amounts of phosphate were not detected. The UBC had an estimated molecular mass by gel filtration chromatography of 15 MDa, and it was proposed to contain 150 heterodimers (UFO1_4203 and UFO1_4202) and about 500 uranium atoms. The UBC was also the dominant extracellular protein, but when purified from the growth medium, it contained only 0.3 U atoms/heterodimer. The two genes encoding the UBC were among the most highly expressed genes within the UFO1 genome, and their expressions were unchanged by the presence or absence of uranium. Therefore, the UBC appears to be constitutively expressed and is the first line of defense against uranium, including by secretion into the extracellular medium. Although S-layer proteins were previously shown to bind U(VI), here we showed that U(IV) binds to S-layer proteins, we identified the proteins involved, and we quantitated the amount of uranium bound. IMPORTANCE Widespread uranium contamination from industrial sources poses hazards to human health and to the environment. Herein, we identified a highly abundant uranium-binding complex (UBC) from Pelosinus sp. strain UFO1. The complex makes up the primary protein component of the S-layer of strain UFO1 and binds 3.3 atoms of U(IV) per heterodimer. While other bacteria have been shown to bind U(VI) on their S-layer, we demonstrate here an example of U(IV) bound by an S-layer complex. The UBC provides a potential tool for the microbiological sequestration of uranium for the cleaning of contaminated environments. PMID:27913415

A Highly Expressed High-Molecular-Weight S-Layer Complex of Pelosinus sp. Strain UFO1 Binds Uranium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thorgersen, Michael P.; Lancaster, W. Andrew; Rajeev, Lara

Cell suspensions of Pelosinus sp. strain UFO1 were previously shown, using spectroscopic analysis, to sequester uranium as U(IV) complexed with carboxyl and phosphoryl group ligands on proteins. The goal of our present study was to characterize the proteins involved in uranium binding. Virtually all of the uranium in UFO1 cells was associated with a heterodimeric protein, which was termed the uranium-binding complex (UBC). The UBC was composed of two S-layer domain proteins encoded by UFO1_4202 and UFO1_4203. Samples of UBC purified from the membrane fraction contained 3.3 U atoms/heterodimer, but significant amounts of phosphate were not detected. The UBC hadmore » an estimated molecular mass by gel filtration chromatography of 15 MDa, and it was proposed to contain 150 heterodimers (UFO1_4203 and UFO1_4202) and about 500 uranium atoms. The UBC was also the dominant extracellular protein, but when purified from the growth medium, it contained only 0.3 U atoms/heterodimer. The two genes encoding the UBC were among the most highly expressed genes within the UFO1 genome, and their expressions were unchanged by the presence or absence of uranium. Therefore, the UBC appears to be constitutively expressed and is the first line of defense against uranium, including by secretion into the extracellular medium. Although S-layer proteins were previously shown to bind U(VI), here we showed that U(IV) binds to S-layer proteins, we identified the proteins involved, and we quantitated the amount of uranium bound. Widespread uranium contamination from industrial sources poses hazards to human health and to the environment. Here in this paper, we identified a highly abundant uranium-binding complex (UBC) from Pelosinus sp. strain UFO1. The complex makes up the primary protein component of the S-layer of strain UFO1 and binds 3.3 atoms of U(IV) per heterodimer. Finally, while other bacteria have been shown to bind U(VI) on their S-layer, we demonstrate here an example of U(IV) bound by an S-layer complex. The UBC provides a potential tool for the microbiological sequestration of uranium for the cleaning of contaminated environments.« less

A Highly Expressed High-Molecular-Weight S-Layer Complex of Pelosinus sp. Strain UFO1 Binds Uranium.

PubMed

Thorgersen, Michael P; Lancaster, W Andrew; Rajeev, Lara; Ge, Xiaoxuan; Vaccaro, Brian J; Poole, Farris L; Arkin, Adam P; Mukhopadhyay, Aindrila; Adams, Michael W W

2017-02-15

Cell suspensions of Pelosinus sp. strain UFO1 were previously shown, using spectroscopic analysis, to sequester uranium as U(IV) complexed with carboxyl and phosphoryl group ligands on proteins. The goal of our present study was to characterize the proteins involved in uranium binding. Virtually all of the uranium in UFO1 cells was associated with a heterodimeric protein, which was termed the uranium-binding complex (UBC). The UBC was composed of two S-layer domain proteins encoded by UFO1_4202 and UFO1_4203. Samples of UBC purified from the membrane fraction contained 3.3 U atoms/heterodimer, but significant amounts of phosphate were not detected. The UBC had an estimated molecular mass by gel filtration chromatography of 15 MDa, and it was proposed to contain 150 heterodimers (UFO1_4203 and UFO1_4202) and about 500 uranium atoms. The UBC was also the dominant extracellular protein, but when purified from the growth medium, it contained only 0.3 U atoms/heterodimer. The two genes encoding the UBC were among the most highly expressed genes within the UFO1 genome, and their expressions were unchanged by the presence or absence of uranium. Therefore, the UBC appears to be constitutively expressed and is the first line of defense against uranium, including by secretion into the extracellular medium. Although S-layer proteins were previously shown to bind U(VI), here we showed that U(IV) binds to S-layer proteins, we identified the proteins involved, and we quantitated the amount of uranium bound. Widespread uranium contamination from industrial sources poses hazards to human health and to the environment. Herein, we identified a highly abundant uranium-binding complex (UBC) from Pelosinus sp. strain UFO1. The complex makes up the primary protein component of the S-layer of strain UFO1 and binds 3.3 atoms of U(IV) per heterodimer. While other bacteria have been shown to bind U(VI) on their S-layer, we demonstrate here an example of U(IV) bound by an S-layer complex. The UBC provides a potential tool for the microbiological sequestration of uranium for the cleaning of contaminated environments. Copyright © 2017 American Society for Microbiology.

Ionic bonding of lanthanides, as influenced by d- and f-atomic orbitals, by core-shells and by relativity.

PubMed

Ji, Wen-Xin; Xu, Wei; Schwarz, W H Eugen; Wang, Shu-Guang

2015-03-15

Lanthanide trihalide molecules LnX3 (X = F, Cl, Br, I) were quantum chemically investigated, in particular detail for Ln = Lu (lutetium). We applied density functional theory (DFT) at the nonrelativistic and scalar and SO-coupled relativistic levels, and also the ab initio coupled cluster approach. The chemically active electron shells of the lanthanide atoms comprise the 5d and 6s (and 6p) valence atomic orbitals (AO) and also the filled inner 4f semivalence and outer 5p semicore shells. Four different frozen-core approximations for Lu were compared: the (1s(2) -4d(10) ) [Pd] medium core, the [Pd+5s(2) 5p(6) = Xe] and [Pd+4f(14) ] large cores, and the [Pd+4f(14) +5s(2) 5p(6) ] very large core. The errors of LuX bonding are more serious on freezing the 5p(6) shell than the 4f(14) shell, more serious upon core-freezing than on the effective-core-potential approximation. The LnX distances correlate linearly with the AO radii of the ionic outer shells, Ln(3+) -5p(6) and X(-) -np(6) , characteristic for dominantly ionic Ln(3+) -X(-) binding. The heavier halogen atoms also bind covalently with the Ln-5d shell. Scalar relativistic effects contract and destabilize the LuX bonds, spin orbit coupling hardly affects the geometries but the bond energies, owing to SO effects in the free atoms. The relativistic changes of bond energy BE, bond length Re , bond force k, and bond stretching frequency vs do not follow the simple rules of Badger and Gordy (Re ∼BE∼k∼vs ). The so-called degeneracy-driven covalence, meaning strong mixing of accidentally near-degenerate, nearly nonoverlapping AOs without BE contribution is critically discussed. © 2015 Wiley Periodicals, Inc.

A molecular dynamics study of the complete binding process of meropenem to New Delhi metallo-β-lactamase 1.

PubMed

Duan, Juan; Hu, Chuncai; Guo, Jiafan; Guo, Lianxian; Sun, Jia; Zhao, Zuguo

2018-02-28

The mechanism of substrate hydrolysis of New Delhi metallo-β-lactamase 1 (NDM-1) has been reported, but the process in which NDM-1 captures and transports the substrate into its active center remains unknown. In this study, we investigated the process of the substrate entry into the NDM-1 activity center through long unguided molecular dynamics simulations using meropenem as the substrate. A total of 550 individual simulations were performed, each of which for 200 ns, and 110 of them showed enzyme-substrate binding events. The results reveal three categories of relatively persistent and noteworthy enzyme-substrate binding configurations, which we call configurations A, B, and C. We performed binding free energy calculations of the enzyme-substrate complexes of different configurations using the molecular mechanics Poisson-Boltzmann surface area method. The role of each residue of the active site in binding the substrate was investigated using energy decomposition analysis. The simulated trajectories provide a continuous atomic-level view of the entire binding process, revealing potentially valuable regions where the enzyme and the substrate interact persistently and five possible pathways of the substrate entering into the active center, which were validated using well-tempered metadynamics. These findings provide important insights into the binding mechanism of meropenem to NDM-1, which may provide new prospects for the design of novel metallo-β-lactamase inhibitors and enzyme-resistant antibiotics.

Characterization of the interaction between diferric transferrin and transferrin receptor 2 by functional assays and atomic force microscopy*

PubMed Central

Ikuta, Katsuya; Yersin, Alexandre; Ikai, Atsushi; Aisen, Philip; Kohgo, Yutaka

2010-01-01

Transferrin receptor (TfR2), a homologue of classical transferrin receptor 1 (TfR1), is found in two isoforms, α and β. Like TfR1, TfR2α is a type II membrane protein, but the β form lacks transmembrane portions and therefore is likely to be an intracellular protein. To investigate the functional properties of TfR2α we expressed the protein with FLAG-tagging in transferrin receptor-deficient Chinese hamster ovary cells. The association constant for binding of diferric transferrin (Tf) to TfR2α is 5.6 × 106 M−1, which is about 50 times lower than that of TfR1, with correspondingly reduced rates of iron uptake. Evidence for Tf internalization and recycling via TfR2α without degradation, as in the TfR1 pathway, was also found. The interaction of TfR2α with Tf was further investigated using atomic force microscopy (AFM), a powerful tool for investigation of the interaction between ligand and receptor at the single molecule level on the living cell surface. Dynamic force microscopy reveals a difference in the interactions of Tf with TfR2α and TfR1, with Tf-TfR1 unbinding characterized by 2 energy barriers, while only one is present for Tf-TfR2. We speculate that this difference may reflect Tf binding to TfR2α by a single lobe, whereas two lobes of Tf participate in binding to TfR1. The difference in the binding properties of Tf to TfR1 and TfR2α may help account for the different physiological roles of the two receptors. PMID:20096706

Allosteric Fine-Tuning of the Binding Pocket Dynamics in the ITK SH2 Domain by a Distal Molecular Switch: An Atomistic Perspective.

PubMed

Momin, Mohamed; Xin, Yao; Hamelberg, Donald

2017-06-29

Although the regulation of function of proteins by allosteric interactions has been identified in many subcellular processes, molecular switches are also known to induce long-range conformational changes in proteins. A less well understood molecular switch involving cis-trans isomerization of a peptidyl-prolyl bond could induce a conformational change directly to the backbone that is propagated to other parts of the protein. However, these switches are elusive and hard to identify because they are intrinsic to biomolecules that are inherently dynamic. Here, we explore the conformational dynamics and free energy landscape of the SH2 domain of interleukin-2-inducible T-cell or tyrosine kinase (ITK) to fully understand the conformational coupling between the distal cis-trans molecular switch and its binding pocket of the phosphotyrosine motif. We use multiple microsecond-long all-atom molecular dynamics simulations in explicit water for over a total of 60 μs. We show that cis-trans isomerization of the Asn286-Pro287 peptidyl-prolyl bond is directly coupled to the dynamics of the binding pocket of the phosphotyrosine motif, in agreement with previous NMR experiments. Unlike the cis state that is localized and less dynamic in a single free energy basin, the trans state samples two distinct conformations of the binding pocket-one that recognizes the phosphotyrosine motif and the other that is somewhat similar to that of the cis state. The results provide an atomic-level description of a less well understood allosteric regulation by a peptidyl-prolyl cis-trans molecular switch that could aid in the understanding of normal and aberrant subcellular processes and the identification of these elusive molecular switches in other proteins.

Stability, surface features, and atom leaching of palladium nanoparticles: toward prediction of catalytic functionality.

PubMed

Ramezani-Dakhel, Hadi; Mirau, Peter A; Naik, Rajesh R; Knecht, Marc R; Heinz, Hendrik

2013-04-21

Surfactant-stabilized metal nanoparticles have shown promise as catalysts although specific surface features and their influence on catalytic performance have not been well understood. We quantify the thermodynamic stability, the facet composition of the surface, and distinct atom types that affect rates of atom leaching for a series of twenty near-spherical Pd nanoparticles of 1.8 to 3.1 nm size using computational models. Cohesive energies indicate higher stability of certain particles that feature an approximate 60/20/20 ratio of {111}, {100}, and {110} facets while less stable particles exhibit widely variable facet composition. Unique patterns of atom types on the surface cause apparent differences in binding energies and changes in reactivity. Estimates of the relative rate of atom leaching as a function of particle size were obtained by the summation of Boltzmann-weighted binding energies over all surface atoms. Computed leaching rates are in good qualitative correlation with the measured catalytic activity of peptide-stabilized Pd nanoparticles of the same shape and size in Stille coupling reactions. The agreement supports rate-controlling contributions by atom leaching in the presence of reactive substrates. The computational approach provides a pathway to estimate the catalytic activity of metal nanostructures of engineered shape and size, and possible further refinements are described.

Stereo-selective binding of chlorobenzene on Si(111)-7×7

NASA Astrophysics Data System (ADS)

Cao, Y.; Deng, J. F.; Xu, G. Q.

2000-03-01

The adsorption and binding of chlorobenzene (C6H5Cl) on clean and D-modified Si(111)-7×7 surfaces have been investigated using high resolution electron energy loss spectroscopy (HREELS) and thermal desorption spectroscopy (TDS). On a clean surface, both chemisorbed and physisorbed C6H5Cl are observed at an adsorption temperature of 110 K. The HREEL spectra show direct evidence for the presence of both sp2 and sp3 carbon atoms in chemisorbed C6H5Cl molecules on Si(111)-7×7. Upon D-modification, the chemisorption of C6H5Cl decreases rapidly with increasing D-coverage (θD). At θD=1/3 ML, only physisorbed chlorobenzene is detected, which strongly suggests the involvement of rest-atoms in the chemisorption of C6H5Cl. Combined with the scanning tunneling microscopy (STM) results by Chen et al. [Surf. Sci. 340, 224 (1995)] showing the participation of adatoms in the binding, we propose that the 2,5-carbon atoms in C6H5Cl are stereo-selectively di-σ bonded to a pair of adjacent adatom and rest-atom on the Si(111)-7×7 surface, yielding a 2,5-chlorocyclohexadienelike surface adduct.

DFT Modeling of Cross-Linked Polyethylene: Role of Gold Atoms and Dispersion Interactions.

PubMed

Blaško, Martin; Mach, Pavel; Antušek, Andrej; Urban, Miroslav

2018-02-08

Using DFT modeling, we analyze the concerted action of gold atoms and dispersion interactions in cross-linked polyethylene. Our model consists of two oligomer chains (PEn) with 7, 11, 15, 19, or 23 carbon atoms in each oligomer cross-linked with one to three Au atoms through C-Au-C bonds. In structures with a single gold atom the C-Au-C bond is located in the central position of the oligomer. Binding energies (BEs) with respect to two oligomer radical fragments and Au are as high as 362-489 kJ/mol depending on the length of the oligomer chain. When the dispersion contribution in PEn-Au-PEn oligomers is omitted, BE is almost independent of the number of carbon atoms, lying between 293 and 296 kJ/mol. The dispersion energy contributions to BEs in PEn-Au-PEn rise nearly linearly with the number of carbon atoms in the PEn chain. The carbon-carbon distance in the C-Au-C moiety is around 4.1 Å, similar to the bond distance between saturated closed shell chains in the polyethylene crystal. BEs of pure saturated closed shell PEn-PEn oligomers are 51-187 kJ/mol. Both Au atoms and dispersion interactions contribute considerably to the creation of nearly parallel chains of oligomers with reasonably high binding energies.

A Model for Predicting Thermoelectric Properties of Bi2Te3

NASA Technical Reports Server (NTRS)

Lee, Seungwon; VonAllmen, Paul

2009-01-01

A parameterized orthogonal tight-binding mathematical model of the quantum electronic structure of the bismuth telluride molecule has been devised for use in conjunction with a semiclassical transport model in predicting the thermoelectric properties of doped bismuth telluride. This model is expected to be useful in designing and analyzing Bi2Te3 thermoelectric devices, including ones that contain such nano - structures as quantum wells and wires. In addition, the understanding gained in the use of this model can be expected to lead to the development of better models that could be useful for developing other thermoelectric materials and devices having enhanced thermoelectric properties. Bi2Te3 is one of the best bulk thermoelectric materials and is widely used in commercial thermoelectric devices. Most prior theoretical studies of the thermoelectric properties of Bi2Te3 have involved either continuum models or ab-initio models. Continuum models are computationally very efficient, but do not account for atomic-level effects. Ab-initio models are atomistic by definition, but do not scale well in that computation times increase excessively with increasing numbers of atoms. The present tight-binding model bridges the gap between the well-scalable but non-atomistic continuum models and the atomistic but poorly scalable ab-initio models: The present tight-binding model is atomistic, yet also computationally efficient because of the reduced (relative to an ab-initio model) number of basis orbitals and flexible parameterization of the Hamiltonian.

Carbon-tuned bonding method significantly enhanced the hydrogen storage of BN-Li complexes.

PubMed

Deng, Qing-ming; Zhao, Lina; Luo, You-hua; Zhang, Meng; Zhao, Li-xia; Zhao, Yuliang

2011-11-01

Through first-principles calculations, we found doping carbon atoms onto BN monolayers (BNC) could significantly strengthen the Li bond on this material. Unlike the weak bond strength between Li atoms and the pristine BN layer, it is observed that Li atoms are strongly hybridized and donate their electrons to the doped substrate, which is responsible for the enhanced binding energy. Li adsorbed on the BNC layer can serve as a high-capacity hydrogen storage medium, without forming clusters, which can be recycled at room temperature. Eight polarized H(2) molecules are attached to two Li atoms with an optimal binding energy of 0.16-0.28 eV/H(2), which results from the electrostatic interaction of the polarized charge of hydrogen molecules with the electric field induced by positive Li atoms. This practical carbon-tuned BN-Li complex can work as a very high-capacity hydrogen storage medium with a gravimetric density of hydrogen of 12.2 wt%, which is much higher than the gravimetric goal of 5.5 wt % hydrogen set by the U.S. Department of Energy for 2015.

Structural Basis for Nucleotide Exchange in Heterotrimeric G Proteins

PubMed Central

Dror, Ron O.; Mildorf, Thomas J.; Hilger, Daniel; Manglik, Aashish; Borhani, David W.; Arlow, Daniel H.; Philippsen, Ansgar; Villanueva, Nicolas; Yang, Zhongyu; Lerch, Michael T.; Hubbell, Wayne L.; Kobilka, Brian K.; Sunahara, Roger K.; Shaw, David E.

2016-01-01

G protein–coupled receptors (GPCRs) relay diverse extracellular signals into cells by catalyzing nucleotide release from heterotrimeric G proteins, but the mechanism underlying this quintessential molecular signaling event has remained unclear. Here we use atomic-level simulations to elucidate the nucleotide-release mechanism. We find that the G protein α subunit Ras and helical domains—previously observed to separate widely upon receptor binding to expose the nucleotide-binding site—separate spontaneously and frequently even in the absence of a receptor. Domain separation is necessary but not sufficient for rapid nucleotide release. Rather, receptors catalyze nucleotide release by favoring an internal structural rearrangement of the Ras domain that weakens its nucleotide affinity. We use double electron-electron resonance spectroscopy and protein engineering to confirm predictions of our computationally determined mechanism. PMID:26089515

Tetrel Bonding as a Vehicle for Strong and Selective Anion Binding.

PubMed

Scheiner, Steve

2018-05-11

Tetrel atoms T (T = Si, Ge, Sn, and Pb) can engage in very strong noncovalent interactions with nucleophiles, which are commonly referred to as tetrel bonds. The ability of such bonds to bind various anions is assessed with a goal of designing an optimal receptor. The Sn atom seems to form the strongest bonds within the tetrel family. It is most effective in the context of a -SnF₃ group and a further enhancement is observed when a positive charge is placed on the receptor. Connection of the -SnF₃ group to either an imidazolium or triazolium provides a strong halide receptor, which can be improved if its point of attachment is changed from the C to an N atom of either ring. Aromaticity of the ring offers no advantage nor is a cyclic system superior to a simple alkyl amine of any chain length. Placing a pair of -SnF₃ groups on a single molecule to form a bipodal dicationic receptor with two tetrel bonds enhances the binding, but falls short of a simple doubling. These two tetrel groups can be placed on opposite ends of an alkyl diamine chain of any length although SnF₃⁺NH₂(CH₂) n NH₂SnF₃⁺ with n between 2 and 4 seems to offer the strongest halide binding. Of the various anions tested, OH − binds most strongly: OH − > F − > Cl − > Br − > I − . The binding energy of the larger NO₃ − and HCO₃ − anions is more dependent upon the charge of the receptor. This pattern translates into very strong selectivity of binding one anion over another. The tetrel-bonding receptors bind far more strongly to each anion than an equivalent number of K⁺ counterions, which leads to equilibrium ratios in favor of the former of many orders of magnitude.

Quantitative structure-activity relationship studies of threo-methylphenidate analogs.

PubMed

Misra, Milind; Shi, Qing; Ye, Xiaocong; Gruszecka-Kowalik, Ewa; Bu, Wei; Liu, Zhanzhu; Schweri, Margaret M; Deutsch, Howard M; Venanzi, Carol A

2010-10-15

Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D- and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure-activity data of the training set indicate that the 2' position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3' or 4' positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3' and 4' position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3',4'-benzo analog, 79. A complementary 2D-QSAR approach-partial least squares analysis using a reduced set of Molconn-Z descriptors-supports the CoMFA structure-activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl)acetate, an analog not in the original data set, to be in good agreement with the experimental value. Copyright © 2010 Elsevier Ltd. All rights reserved.

Stiffening of flexible SUMO1 protein upon peptide-binding: Analysis with anisotropic network model.

PubMed

Sarkar, Ranja

2018-01-01

SUMO (small ubiquitin-like modifier) proteins interact with a large number of target proteins via a key regulatory event called sumoylation that encompasses activation, conjugation and ligation of SUMO proteins through specific E1, E2, and E3-type enzymes respectively. Single-molecule atomic force microscopic (AFM) experiments performed to unravel bound SUMO1 along its NC termini direction reveal that E3-ligases (in the form of small peptides) increase mechanical stability (along the axis) of the flexible protein upon binding. The experimental results are expected to correlate with the intrinsic flexibility of bound SUMO1 protein in the native state i.e., the bound conformation of SUMO1 without the binding peptide. The native protein flexibility/stiffness can be measured as a spring constant by normal mode analysis. In the present study, protein normal modes are computed from the protein structural data (as input from protein databank) via a simple anisotropic network model (ANM). ANM is computationally inexpensive and hence, can be explored to investigate and compare the native conformational dynamics of unbound and bound (without the binding partner) structures, if the corresponding structural data (NMR/X-ray) are available. The paper illustrates that SUMO1 stiffens (native flexibility decreases) along the NC termini (end-to-end) direction of the protein upon binding to small peptides; however, the degree of stiffening is peptide sequence-specific. The theoretical results are demonstrated for NMR structures of unbound SUMO1 and that bound to two peptides having short amino acid motifs and of similar size, one being an M-IR2 peptide derived from RanBP2 protein and the other one derived from PIASX protein. The peptide derived from PIASX stiffens SUMO1 remarkably which is evident from an atomic-level normal mode analysis. Copyright © 2017 Elsevier Inc. All rights reserved.

Activity of N-coordinated multi-metal-atom active site structures for Pt-free oxygen reduction reaction catalysis: Role of *OH ligands

DOE PAGES

Holby, Edward F.; Taylor, Christopher D.

2015-03-19

We report calculated oxygen reduction reaction energy pathways on multi-metal-atom structures that have previously been shown to be thermodynamically favorable. We predict that such sites have the ability to spontaneously cleave the O₂ bond and then will proceed to over-bind reaction intermediates. In particular, the *OH bound state has lower energy than the final 2 H₂O state at positive potentials. Contrary to traditional surface catalysts, this *OH binding does not poison the multi-metal-atom site but acts as a modifying ligand that will spontaneously form in aqueous environments leading to new active sites that have higher catalytic activities. These *OH boundmore » structures have the highest calculated activity to date.« less

Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis.

PubMed

Luna-Zurita, Luis; Stirnimann, Christian U; Glatt, Sebastian; Kaynak, Bogac L; Thomas, Sean; Baudin, Florence; Samee, Md Abul Hassan; He, Daniel; Small, Eric M; Mileikovsky, Maria; Nagy, Andras; Holloway, Alisha K; Pollard, Katherine S; Müller, Christoph W; Bruneau, Benoit G

2016-02-25

Transcription factors (TFs) are thought to function with partners to achieve specificity and precise quantitative outputs. In the developing heart, heterotypic TF interactions, such as between the T-box TF TBX5 and the homeodomain TF NKX2-5, have been proposed as a mechanism for human congenital heart defects. We report extensive and complex interdependent genomic occupancy of TBX5, NKX2-5, and the zinc finger TF GATA4 coordinately controlling cardiac gene expression, differentiation, and morphogenesis. Interdependent binding serves not only to co-regulate gene expression but also to prevent TFs from distributing to ectopic loci and activate lineage-inappropriate genes. We define preferential motif arrangements for TBX5 and NKX2-5 cooperative binding sites, supported at the atomic level by their co-crystal structure bound to DNA, revealing a direct interaction between the two factors and induced DNA bending. Complex interdependent binding mechanisms reveal tightly regulated TF genomic distribution and define a combinatorial logic for heterotypic TF regulation of differentiation. Copyright © 2016 Elsevier Inc. All rights reserved.

Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations

PubMed Central

Yu, Zhe; Ma, Yu-chi; Ai, Jing; Chen, Dan-qi; Zhao, Dong-mei; Wang, Xin; Chen, Yue-lei; Geng, Mei-yu; Xiong, Bing; Cheng, Mao-sheng; Shen, Jing-kang

2013-01-01

Aim: To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors. Methods: Based on the prototype model inhibitor 1, four ligands with subtle differences in the fused aromatic rings were synthesized. Quantum chemistry was employed to calculate the binding free energy for each ligand. Symmetry-adapted perturbation theory (SAPT) was used to decompose the binding energy into several fundamental forces to elucidate the determinant factors. Results: Binding free energies calculated from quantum chemistry were correlated well with experimental data. SAPT calculations showed that the predominant driving force for binding was derived from a sandwich π–π interaction with Tyr-1230. Arg-1208 was the differentiating factor, interacting with the 6-position of the fused aromatic ring system through the backbone carbonyl with a force pattern similar to hydrogen bonding. Therefore, a hydrogen atom must be attached at the 6-position, and changing the carbon atom to nitrogen caused unfavorable electrostatic interactions. Conclusion: The theoretical studies have elucidated the determinant factors involved in the binding of type I inhibitors to c-Met. PMID:24056705

Identification of Binding Modes for Amino Naphthalene 2-Cyanoacrylate (ANCA) Probes to Amyloid Fibrils from Molecular Dynamics Simulations.

PubMed

He, Huan; Xu, Juan; Cheng, Dan-Yang; Fu, Li; Ge, Yu-Shu; Jiang, Feng-Lei; Liu, Yi

2017-02-16

The amino naphthalene 2-cyanoacrylate (ANCA) probe is a kind of fluorescent amyloid binding probe that can report different fluorescence emissions when bound to various amyloid deposits in tissue, while their interactions with amyloid fibrils remain unclear due to the insoluble nature of amyloid fibrils. Here, all-atom molecular dynamics simulations were used to investigate the interaction between ANCA probes with three different amyloid fibrils. Two common binding modes of ANCA probes on Aβ40 amyloid fibrils were identified by cluster analysis of multiple simulations. The van der Waals and electrostatic interactions were found to be major driving forces for the binding. Atomic contacts analysis and binding free energy decomposition results suggested that the hydrophobic part of ANCA mainly interacts with aromatic side chains on the fibril surface and the hydrophilic part mainly interacts with positive charged residues in the β-sheet region. By comparing the binding modes with different fibrils, we can find that ANCA adopts different conformations while interacting with residues of different hydrophobicity, aromaticity, and electrochemical properties in the β-sheet region, which accounts for its selective mechanism toward different amyloid fibrils.

Computational evaluation of sub-nanometer cluster activity of singly exposed copper atom with various coordinative environment in catalytic CO2 transformation

NASA Astrophysics Data System (ADS)

Shanmugam, Ramasamy; Thamaraichelvan, Arunachalam; Ganesan, Tharumeya Kuppusamy; Viswanathan, Balasubramanian

2017-02-01

Metal cluster, at sub-nanometer level has a unique property in the activation of small molecules, in contrast to that of bulk surface. In the present work, singly exposed active site of copper metal cluster at sub-nanometer level was designed to arrive at the energy minimised configurations, binding energy, electrostatic potential map, frontier molecular orbitals and partial density of states. The ab initio molecular dynamics was carried out to probe the catalytic nature of the cluster. Further, the stability of the metal cluster and its catalytic activity in the electrochemical reduction of CO2 to CO were evaluated by means of computational hydrogen electrode via calculation of the free energy profile using DFT/B3LYP level of theory in vacuum. The activity of the cluster is ascertained from the fact that the copper atom, present in a two coordinative environment, performs a more selective conversion of CO2 to CO at an applied potential of -0.35 V which is comparatively lower than that of higher coordinative sites. The present study helps to design any sub-nano level metal catalyst for electrochemical reduction of CO2 to various value added chemicals.

Hydrogen incorporation into BN fullerene-like nanostructures: A first-principles study

NASA Astrophysics Data System (ADS)

Ganji, M. D.; Abbaszadeh, B.; Ahaz, B.

2011-10-01

We performed density functional theory calculations to investigate the possibility of formation of endohedrally H@(BN) n-fullerene ( n: 24, 36, 60) and H@C 60 complexes for potential applications in solid-state quantum-computers. Spin-polarized approach within the generalized gradient approximation with the Perdew-Burke-Ernzerhof functional was used for the total energies and structural relaxation calculations. The calculated binding energies show that H atom being incorporated into B 60N 60 nanocage can form most stable complexes while the B 24N 24 and C 60 nanocages might form unstable complex with positive binding energy. We have also examined the penetration of an H atom into the respective nanocages and the calculated barrier energies indicate that the H atom prefers to penetrate into the B 24N 24 and B 60N 60 nanocages with barrier energy of about 0.47 eV (10.84 kcal/mol). Furthermore the binding characteristic is rationalized by analyzing the electronic structures. Our findings reveal that the B 60N 60 nanocage has fascinating potential application in future solid-state quantum-computers.

Neutron diffraction of acetazolamide-bound human carbonic anhydrase II reveals atomic details of drug binding

PubMed Central

Fisher, S. Zoë; Aggarwal, Mayank; Kovalevsky, Andrey Y.; Silverman, David N.; McKenna, Robert

2012-01-01

Carbonic anhydrases (CAs) catalyze the hydration of CO2 forming HCO3− and a proton, an important reaction for many physiological processes including respiration, fluid secretion, and pH regulation. As such, CA isoforms are prominent clinical targets for treating various diseases. The clinically used acetazolamide (AZM) is a sulfonamide that binds with high affinity to human CA isoform II (HCA II). There are several X-ray structures available of AZM bound to various CA isoforms, but these complexes do not show the charged state of AZM, or hydrogen (H) atom positions of the protein and solvent. Neutron diffraction is a useful technique for directly observing H atoms and the mapping of H-bonding networks that can greatly contribute to rational drug design. To this end the neutron structure of H/D exchanged HCA II crystals in complex with AZM was determined. The structure reveals the molecular details of AZM binding and the charged state of the bound drug. This represents the first determined neutron structure of a clinically used drug bound to its target. PMID:22928733

Membrane Destruction and DNA Binding of Staphylococcus aureus Cells Induced by Carvacrol and Its Combined Effect with a Pulsed Electric Field.

PubMed

Wang, Lang-Hong; Wang, Man-Sheng; Zeng, Xin-An; Zhang, Zhi-Hong; Gong, De-Ming; Huang, Yan-Bo

2016-08-17

Carvacrol (5-isopropyl-2-methylphenol, CAR) is an antibacterial ingredient that occurs naturally in the leaves of the plant Origanum vulgare. The antimicrobial mechanism of CAR against Staphylococcus aureus ATCC 43300 was investigated in the study. Analysis of the membrane fatty acids by gas chromatography-mass spectrometry (GC-MS) showed that exposure to CAR at low concentrations induced a marked increase in the level of unbranched fatty acids (from 34.90 ± 1.77% to 62.37 ± 4.26%). Moreover, CAR at higher levels severely damaged the integrity and morphologies of the S. aureus cell membrane. The DNA-binding properties of CAR were also investigated using fluorescence, circular dichroism, molecular modeling, and atomic-force microscopy. The results showed that CAR bound to DNA via the minor-groove mode, mildly perturbed the DNA secondary structure, and induced DNA molecules to be aggregated. Furthermore, a combination of CAR with a pulsed-electric field was found to exhibit strong synergistic effects on S. aureus.

The structure and binding mode of citrate in the stabilization of gold nanoparticles

NASA Astrophysics Data System (ADS)

Al-Johani, Hind; Abou-Hamad, Edy; Jedidi, Abdesslem; Widdifield, Cory M.; Viger-Gravel, Jasmine; Sangaru, Shiv Shankar; Gajan, David; Anjum, Dalaver H.; Ould-Chikh, Samy; Hedhili, Mohamed Nejib; Gurinov, Andrei; Kelly, Michael J.; El Eter, Mohamad; Cavallo, Luigi; Emsley, Lyndon; Basset, Jean-Marie

2017-09-01

Elucidating the binding mode of carboxylate-containing ligands to gold nanoparticles (AuNPs) is crucial to understand their stabilizing role. A detailed picture of the three-dimensional structure and coordination modes of citrate, acetate, succinate and glutarate to AuNPs is obtained by 13C and 23Na solid-state NMR in combination with computational modelling and electron microscopy. The binding between the carboxylates and the AuNP surface is found to occur in three different modes. These three modes are simultaneously present at low citrate to gold ratios, while a monocarboxylate monodentate (1κO1) mode is favoured at high citrate:gold ratios. The surface AuNP atoms are found to be predominantly in the zero oxidation state after citrate coordination, although trace amounts of Auδ+ are observed. 23Na NMR experiments show that Na+ ions are present near the gold surface, indicating that carboxylate binding occurs as a 2e- L-type interaction for each oxygen atom involved. This approach has broad potential to probe the binding of a variety of ligands to metal nanoparticles.

Cavity Versus Ligand Shape Descriptors: Application to Urokinase Binding Pockets

PubMed Central

Cerisier, Natacha; Regad, Leslie; Triki, Dhoha; Camproux, Anne-Claude

2017-01-01

Abstract We analyzed 78 binding pockets of the human urokinase plasminogen activator (uPA) catalytic domain extracted from a data set of crystallized uPA–ligand complexes. These binding pockets were computed with an original geometric method that does NOT involve any arbitrary parameter, such as cutoff distances, angles, and so on. We measured the deviation from convexity of each pocket shape with the pocket convexity index (PCI). We defined a new pocket descriptor called distributional sphericity coefficient (DISC), which indicates to which extent the protein atoms of a given pocket lie on the surface of a sphere. The DISC values were computed with the freeware PCI. The pocket descriptors and their high correspondences with ligand descriptors are crucial for polypharmacology prediction. We found that the protein heavy atoms lining the urokinases binding pockets are either located on the surface of their convex hull or lie close to this surface. We also found that the radii of the urokinases binding pockets and the radii of their ligands are highly correlated (r = 0.9). PMID:28570103

Different binding mechanisms of neutral and anionic poly-/perfluorinated chemicals to human transthyretin revealed by In silico models.

PubMed

Yang, Xianhai; Lyakurwa, Felichesmi; Xie, Hongbin; Chen, Jingwen; Li, Xuehua; Qiao, Xianliang; Cai, Xiyun

2017-09-01

Chemical forms-dependent binding interactions between phenolic compounds and human transthyretin (hTTR) have been elaborated previously. However, it is not known whether the binding interactions between ionizable halogenated alphatic compounds and hTTR also have the same manner. In this study, poly-/perfluorinated chemicals (PFCs) were selected as model compounds and molecular dynamic simulation was performed to investigate the binding mechanisms between PFCs and hTTR. Results show the binding interactions between the halogenated aliphatic compounds and hTTR are related to the chemical forms. The ionized groups of PFCs can form electrostatic interactions with the -NH + 3 groups of Lys 15 residues in hTTR and form hydrogen bonds with the residues of hTTR. By analyzing the molecular orbital energies of PFCs, we also found that the anionic groups (nucleophile) in PFCs could form electron donor - acceptor interactions with the -NH + 3 groups (electrophile) in Lys 15. The aforementioned orientational interactions make the ionized groups of the PFCs point toward the entry port of the binding site. The roles of fluorine atoms in the binding interactions were also explored. The fluorine atoms can influence the binding interactions via inductive effects. Appropriate molecular descriptors were selected to characterize these interactions, and two quantitative structure-activity relationship models were developed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dual chain synthetic heparin-binding growth factor analogs

DOEpatents

Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY

2012-04-24

The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

Dual chain synthetic heparin-binding growth factor analogs

DOEpatents

Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY

2009-10-06

The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

Reversibly bound chloride in the atrial natriuretic peptide receptor hormone-binding domain: possible allosteric regulation and a conserved structural motif for the chloride-binding site.

PubMed

Ogawa, Haruo; Qiu, Yue; Philo, John S; Arakawa, Tsutomu; Ogata, Craig M; Misono, Kunio S

2010-03-01

The binding of atrial natriuretic peptide (ANP) to its receptor requires chloride, and it is chloride concentration dependent. The extracellular domain (ECD) of the ANP receptor (ANPR) contains a chloride near the ANP-binding site, suggesting a possible regulatory role. The bound chloride, however, is completely buried in the polypeptide fold, and its functional role has remained unclear. Here, we have confirmed that chloride is necessary for ANP binding to the recombinant ECD or the full-length ANPR expressed in CHO cells. ECD without chloride (ECD(-)) did not bind ANP. Its binding activity was fully restored by bromide or chloride addition. A new X-ray structure of the bromide-bound ECD is essentially identical to that of the chloride-bound ECD. Furthermore, bromide atoms are localized at the same positions as chloride atoms both in the apo and in the ANP-bound structures, indicating exchangeable and reversible halide binding. Far-UV CD and thermal unfolding data show that ECD(-) largely retains the native structure. Sedimentation equilibrium in the absence of chloride shows that ECD(-) forms a strongly associated dimer, possibly preventing the structural rearrangement of the two monomers that is necessary for ANP binding. The primary and tertiary structures of the chloride-binding site in ANPR are highly conserved among receptor-guanylate cyclases and metabotropic glutamate receptors. The chloride-dependent ANP binding, reversible chloride binding, and the highly conserved chloride-binding site motif suggest a regulatory role for the receptor bound chloride. Chloride-dependent regulation of ANPR may operate in the kidney, modulating ANP-induced natriuresis.

Reversibly Bound Chloride in the Atrial Natriuretic Peptide Receptor Hormone Binding Domain: Possible Allosteric Regulation and a Conserved Structural Motif for the Chloride-binding Site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ogawa, H.; Qiu, Y; Philo, J

2010-01-01

The binding of atrial natriuretic peptide (ANP) to its receptor requires chloride, and it is chloride concentration dependent. The extracellular domain (ECD) of the ANP receptor (ANPR) contains a chloride near the ANP-binding site, suggesting a possible regulatory role. The bound chloride, however, is completely buried in the polypeptide fold, and its functional role has remained unclear. Here, we have confirmed that chloride is necessary for ANP binding to the recombinant ECD or the full-length ANPR expressed in CHO cells. ECD without chloride (ECD(-)) did not bind ANP. Its binding activity was fully restored by bromide or chloride addition. Amore » new X-ray structure of the bromide-bound ECD is essentially identical to that of the chloride-bound ECD. Furthermore, bromide atoms are localized at the same positions as chloride atoms both in the apo and in the ANP-bound structures, indicating exchangeable and reversible halide binding. Far-UV CD and thermal unfolding data show that ECD(-) largely retains the native structure. Sedimentation equilibrium in the absence of chloride shows that ECD(-) forms a strongly associated dimer, possibly preventing the structural rearrangement of the two monomers that is necessary for ANP binding. The primary and tertiary structures of the chloride-binding site in ANPR are highly conserved among receptor-guanylate cyclases and metabotropic glutamate receptors. The chloride-dependent ANP binding, reversible chloride binding, and the highly conserved chloride-binding site motif suggest a regulatory role for the receptor bound chloride. Chloride-dependent regulation of ANPR may operate in the kidney, modulating ANP-induced natriuresis.« less

Reversibly bound chloride in the atrial natriuretic peptide receptor hormone-binding domain: Possible allosteric regulation and a conserved structural motif for the chloride-binding site

PubMed Central

Ogawa, Haruo; Qiu, Yue; Philo, John S; Arakawa, Tsutomu; Ogata, Craig M; Misono, Kunio S

2010-01-01

The binding of atrial natriuretic peptide (ANP) to its receptor requires chloride, and it is chloride concentration dependent. The extracellular domain (ECD) of the ANP receptor (ANPR) contains a chloride near the ANP-binding site, suggesting a possible regulatory role. The bound chloride, however, is completely buried in the polypeptide fold, and its functional role has remained unclear. Here, we have confirmed that chloride is necessary for ANP binding to the recombinant ECD or the full-length ANPR expressed in CHO cells. ECD without chloride (ECD(−)) did not bind ANP. Its binding activity was fully restored by bromide or chloride addition. A new X-ray structure of the bromide-bound ECD is essentially identical to that of the chloride-bound ECD. Furthermore, bromide atoms are localized at the same positions as chloride atoms both in the apo and in the ANP-bound structures, indicating exchangeable and reversible halide binding. Far-UV CD and thermal unfolding data show that ECD(−) largely retains the native structure. Sedimentation equilibrium in the absence of chloride shows that ECD(−) forms a strongly associated dimer, possibly preventing the structural rearrangement of the two monomers that is necessary for ANP binding. The primary and tertiary structures of the chloride-binding site in ANPR are highly conserved among receptor-guanylate cyclases and metabotropic glutamate receptors. The chloride-dependent ANP binding, reversible chloride binding, and the highly conserved chloride-binding site motif suggest a regulatory role for the receptor bound chloride. Chloride-dependent regulation of ANPR may operate in the kidney, modulating ANP-induced natriuresis. PMID:20066666

Diversity of Cyclic Di-GMP-Binding Proteins and Mechanisms

PubMed Central

2015-01-01

ABSTRACT Cyclic di-GMP (c-di-GMP) synthetases and hydrolases (GGDEF, EAL, and HD-GYP domains) can be readily identified in bacterial genome sequences by using standard bioinformatic tools. In contrast, identification of c-di-GMP receptors remains a difficult task, and the current list of experimentally characterized c-di-GMP-binding proteins is likely incomplete. Several classes of c-di-GMP-binding proteins have been structurally characterized; for some others, the binding sites have been identified; and for several potential c-di-GMP receptors, the binding sites remain to be determined. We present here a comparative structural analysis of c-di-GMP-protein complexes that aims to discern the common themes in the binding mechanisms that allow c-di-GMP receptors to bind it with (sub)micromolar affinities despite the 1,000-fold excess of GTP. The available structures show that most receptors use their Arg and Asp/Glu residues to bind c-di-GMP monomers, dimers, or tetramers with stacked guanine bases. The only exception is the EAL domains that bind c-di-GMP monomers in an extended conformation. We show that in c-di-GMP-binding signature motifs, Arg residues bind to the O-6 and N-7 atoms at the Hoogsteen edge of the guanine base, while Asp/Glu residues bind the N-1 and N-2 atoms at its Watson-Crick edge. In addition, Arg residues participate in stacking interactions with the guanine bases of c-di-GMP and the aromatic rings of Tyr and Phe residues. This may account for the presence of Arg residues in the active sites of every receptor protein that binds stacked c-di-GMP. We also discuss the implications of these structural data for the improved understanding of the c-di-GMP signaling mechanisms. PMID:26055114

Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations.

PubMed

Lu, Haiting; Huang, Xiaoqin; AbdulHameed, Mohamed Diwan M; Zhan, Chang-Guo

2014-04-01

Molecular dynamics (MD) simulations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations have been performed to explore the dynamic behaviors of cytochrome P450 2A6 (CYP2A6) binding with nicotine analogs (that are typical inhibitors) and to calculate their binding free energies in combination with Poisson-Boltzmann surface area (PBSA) calculations. The combined MD simulations and QM/MM-PBSA calculations reveal that the most important structural parameters affecting the CYP2A6-inhibitor binding affinity are two crucial internuclear distances, that is, the distance between the heme iron atom of CYP2A6 and the coordinating atom of the inhibitor, and the hydrogen-bonding distance between the N297 side chain of CYP2A6 and the pyridine nitrogen of the inhibitor. The combined MD simulations and QM/MM-PBSA calculations have led to dynamic CYP2A6-inhibitor binding structures that are consistent with the observed dynamic behaviors and structural features of CYP2A6-inhibitor binding, and led to the binding free energies that are in good agreement with the experimentally-derived binding free energies. The agreement between the calculated binding free energies and the experimentally-derived binding free energies suggests that the combined MD and QM/MM-PBSA approach may be used as a valuable tool to accurately predict the CYP2A6-inhibitor binding affinities in future computational design of new, potent and selective CYP2A6 inhibitors. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mechanism of dissolution of a lithium salt in an electrolytic solvent in a lithium ion secondary battery: a direct ab initio molecular dynamics (AIMD) study.

PubMed

Tachikawa, Hiroto

2014-06-06

The mechanism of dissolution of the Li(+) ion in an electrolytic solvent is investigated by the direct ab initio molecular dynamics (AIMD) method. Lithium fluoroborate (Li(+)BF4(-)) and ethylene carbonate (EC) are examined as the origin of the Li(+) ion and the solvent molecule, respectively. This salt is widely utilized as the electrolyte in the lithium ion secondary battery. The binding of EC to the Li(+) moiety of the Li(+)BF4(-) salt is exothermic, and the binding energies at the CAM-B3LYP/6-311++G(d,p) level for n=1, 2, 3, and 4, where n is the number of EC molecules binding to the Li(+) ion, (EC)n(Li(+)BF4(-)), are calculated to be 91.5, 89.8, 87.2, and 84.0 kcal mol(-1) (per EC molecule), respectively. The intermolecular distances between Li(+) and the F atom of BF4(-) are elongated: 1.773 Å (n=0), 1.820 Å (n=1), 1.974 Å (n=2), 1.942 Å (n=3), and 4.156 Å (n=4). The atomic bond populations between Li(+) and the F atom for n=0, 1, 2, 3, and 4 are 0.202, 0.186, 0.150, 0.038, and 0.0, respectively. These results indicate that the interaction of Li(+) with BF4(-) becomes weaker as the number of EC molecules is increased. The direct AIMD calculation for n=4 shows that EC reacts spontaneously with (EC)3(Li(+)BF4(-)) and the Li(+) ion is stripped from the salt. The following substitution reaction takes place: EC+(EC)3(Li(+)BF4(-))→(EC)4Li(+)-(BF4(-)). The reaction mechanism is discussed on the basis of the theoretical results. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Partially ionized hydrogen plasma in strong magnetic fields.

PubMed

Potekhin, A Y; Chabrier, G; Shibanov, Y A

1999-08-01

We study the thermodynamic properties of a partially ionized hydrogen plasma in strong magnetic fields, B approximately 10(12)-10(13) G, typical of neutron stars. The properties of the plasma depend significantly on the quantum-mechanical sizes and binding energies of the atoms, which are strongly modified by thermal motion across the field. We use new fitting formulas for the atomic binding energies and sizes, based on accurate numerical calculations and valid for any state of motion of the atom. In particular, we take into account decentered atomic states, neglected in previous studies of thermodynamics of magnetized plasmas. We also employ analytic fits for the thermodynamic functions of nonideal fully ionized electron-ion Coulomb plasmas. This enables us to construct an analytic model of the free energy. An ionization equilibrium equation is derived, taking into account the strong magnetic field effects and the nonideality effects. This equation is solved by an iteration technique. Ionization degrees, occupancies, and the equation of state are calculated.

Probing Long-Range Neutrino-Mediated Forces with Atomic and Nuclear Spectroscopy.

PubMed

Stadnik, Yevgeny V

2018-06-01

The exchange of a pair of low-mass neutrinos between electrons, protons, and neutrons produces a "long-range" 1/r^{5} potential, which can be sought for in phenomena originating on the atomic and subatomic length scales. We calculate the effects of neutrino-pair exchange on transition and binding energies in atoms and nuclei. In the case of atomic s-wave states, there is a large enhancement of the induced energy shifts due to the lack of a centrifugal barrier and the highly singular nature of the neutrino-mediated potential. We derive limits on neutrino-mediated forces from measurements of the deuteron binding energy and transition energies in positronium, muonium, hydrogen, and deuterium, as well as isotope-shift measurements in calcium ions. Our limits improve on existing constraints on neutrino-mediated forces from experiments that search for new macroscopic forces by 18 orders of magnitude. Future spectroscopy experiments have the potential to probe long-range forces mediated by the exchange of pairs of standard-model neutrinos and other weakly charged particles.

Probing Long-Range Neutrino-Mediated Forces with Atomic and Nuclear Spectroscopy

NASA Astrophysics Data System (ADS)

Stadnik, Yevgeny V.

2018-06-01

The exchange of a pair of low-mass neutrinos between electrons, protons, and neutrons produces a "long-range" 1 /r5 potential, which can be sought for in phenomena originating on the atomic and subatomic length scales. We calculate the effects of neutrino-pair exchange on transition and binding energies in atoms and nuclei. In the case of atomic s -wave states, there is a large enhancement of the induced energy shifts due to the lack of a centrifugal barrier and the highly singular nature of the neutrino-mediated potential. We derive limits on neutrino-mediated forces from measurements of the deuteron binding energy and transition energies in positronium, muonium, hydrogen, and deuterium, as well as isotope-shift measurements in calcium ions. Our limits improve on existing constraints on neutrino-mediated forces from experiments that search for new macroscopic forces by 18 orders of magnitude. Future spectroscopy experiments have the potential to probe long-range forces mediated by the exchange of pairs of standard-model neutrinos and other weakly charged particles.

Structure and Stability of GeAu{sub n}, n = 1-10 clusters: A Density Functional Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Priyanka,; Dharamvir, Keya; Sharma, Hitesh

2011-12-12

The structures of Germanium doped gold clusters GeAu{sub n} (n = 1-10) have been investigated using ab initio calculations based on density functional theory (DFT). We have obtained ground state geometries of GeAu{sub n} clusters and have it compared with Silicon doped gold clusters and pure gold clusters. The ground state geometries of the GeAu{sub n} clusters show patterns similar to silicon doped gold clusters except for n = 5, 6 and 9. The introduction of germanium atom increases the binding energy of gold clusters. The binding energy per atom of germanium doped cluster is smaller than the corresponding siliconmore » doped gold cluster. The HUMO-LOMO gap for Au{sub n}Ge clusters have been found to vary between 0.46 eV-2.09 eV. The mullikan charge analysis indicates that charge of order of 0.1e always transfers from germanium atom to gold atom.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bai, Rui; Yi, Shaoqiong; Zhang, Xuejie

Highlights: • We evaluated both single molecule binding ability and expression level of 4 ICAM-1 mutations. • AFM was used to measure single-molecule binding ability on living cells. • The SNP of ICAM-1 may induce changes in expressions rather than single-molecule binding ability. - Abstract: Atherosclerosis (As) is characterized by chronic inflammation and is a major cause of human mortality. ICAM-1-mediated adhesion of leukocytes in vessel walls plays an important role in the pathogenesis of atherosclerosis. Two single nucleotide polymorphisms (SNPs) of human intercellular adhesion molecule-1 (ICAM-1), G241R and K469E, are associated with a number of inflammatory diseases. SNP inducedmore » changes in ICAM-1 function rely not only on the expression level but also on the single-molecule binding ability which may be affected by single molecule conformation variations such as protein splicing and folding. Previous studies have shown associations between G241R/K469E polymorphisms and ICAM-1 gene expression. Nevertheless, few studies have been done that focus on the single-molecule forces of the above SNPs and their ligands. In the current study, we evaluated both single molecule binding ability and expression level of 4 ICAM-1 mutations – GK (G241/K469), GE (G241/E469), RK (R241/K469) and RE (R241/E469). No difference in adhesion ability was observed via cell adhesion assay or atomic force microscopy (AFM) measurement when comparing the GK, GE, RK, or RE genotypes of ICAM-1 to each other. On the other hand, flow cytometry suggested that there was significantly higher expression of GE genotype of ICAM-1 on transfected CHO cells. Thus, we concluded that genetic susceptibility to diseases related to ICAM-1 polymorphisms, G241R or K469E, might be due to the different expressions of ICAM-1 variants rather than to the single-molecule binding ability of ICAM-1.« less

Phosphate forms an unusual tripodal complex with the Fe–Mn center of sweet potato purple acid phosphatase

PubMed Central

Schenk, Gerhard; Gahan, Lawrence R.; Carrington, Lyle E.; Mitić, Nataša; Valizadeh, Mohsen; Hamilton, Susan E.; de Jersey, John; Guddat, Luke W.

2005-01-01

Purple acid phosphatases (PAPs) are a family of binuclear metalloenzymes that catalyze the hydrolysis of phosphoric acid esters and anhydrides. A PAP in sweet potato has a unique, strongly antiferromagnetically coupled Fe(III)–Mn(II) center and is distinguished from other PAPs by its increased catalytic efficiency for a range of activated and unactivated phosphate esters, its strict requirement for Mn(II), and the presence of a μ-oxo bridge at pH 4.90. This enzyme displays maximum catalytic efficiency (kcat/Km) at pH 4.5, whereas its catalytic rate constant (kcat) is maximal at near-neutral pH, and, in contrast to other PAPs, its catalytic parameters are not dependent on the pKa of the leaving group. The crystal structure of the phosphate-bound Fe(III)–Mn(II) PAP has been determined to 2.5-Å resolution (final Rfree value of 0.256). Structural comparisons of the active site of sweet potato, red kidney bean, and mammalian PAPs show several amino acid substitutions in the sweet potato enzyme that can account for its increased catalytic efficiency. The phosphate molecule binds in an unusual tripodal mode to the two metal ions, with two of the phosphate oxygen atoms binding to Fe(III) and Mn(II), a third oxygen atom bridging the two metal ions, and the fourth oxygen pointing toward the substrate binding pocket. This binding mode is unique among the known structures in this family but is reminiscent of phosphate binding to urease and of sulfate binding to λ protein phosphatase. The structure and kinetics support the hypothesis that the bridging oxygen atom initiates hydrolysis. PMID:15625111

A periodic pattern of evolutionarily conserved basic and acidic residues constitutes the binding interface of actin-tropomyosin.

PubMed

Barua, Bipasha; Fagnant, Patricia M; Winkelmann, Donald A; Trybus, Kathleen M; Hitchcock-DeGregori, Sarah E

2013-04-05

Actin filament cytoskeletal and muscle functions are regulated by actin binding proteins using a variety of mechanisms. A universal actin filament regulator is the protein tropomyosin, which binds end-to-end along the length of the filament. The actin-tropomyosin filament structure is unknown, but there are atomic models in different regulatory states based on electron microscopy reconstructions, computational modeling of actin-tropomyosin, and docking of atomic resolution structures of tropomyosin to actin filament models. Here, we have tested models of the actin-tropomyosin interface in the "closed state" where tropomyosin binds to actin in the absence of myosin or troponin. Using mutagenesis coupled with functional analyses, we determined residues of actin and tropomyosin required for complex formation. The sites of mutations in tropomyosin were based on an evolutionary analysis and revealed a pattern of basic and acidic residues in the first halves of the periodic repeats (periods) in tropomyosin. In periods P1, P4, and P6, basic residues are most important for actin affinity, in contrast to periods P2, P3, P5, and P7, where both basic and acidic residues or predominantly acidic residues contribute to actin affinity. Hydrophobic interactions were found to be relatively less important for actin binding. We mutated actin residues in subdomains 1 and 3 (Asp(25)-Glu(334)-Lys(326)-Lys(328)) that are poised to make electrostatic interactions with the residues in the repeating motif on tropomyosin in the models. Tropomyosin failed to bind mutant actin filaments. Our mutagenesis studies provide the first experimental support for the atomic models of the actin-tropomyosin interface.

The effect of defects on the catalytic activity of single Au atom supported carbon nanotubes and reaction mechanism for CO oxidation.

PubMed

Ali, Sajjad; Fu Liu, Tian; Lian, Zan; Li, Bo; Sheng Su, Dang

2017-08-23

The mechanism of CO oxidation by O 2 on a single Au atom supported on pristine, mono atom vacancy (m), di atom vacancy (di) and the Stone Wales defect (SW) on single walled carbon nanotube (SWCNT) surface is systematically investigated theoretically using density functional theory. We determine that single Au atoms can be trapped effectively by the defects on SWCNTs. The defects on SWCNTs can enhance both the binding strength and catalytic activity of the supported single Au atom. Fundamental aspects such as adsorption energy and charge transfer are elucidated to analyze the adsorption properties of CO and O 2 and co-adsorption of CO and O 2 molecules. It is found that CO binds stronger than O 2 on Au supported SWCNT. We clearly demonstrate that the defected SWCNT surface promotes electron transfer from the supported single Au atom to O 2 molecules. On the other hand, this effect is weaker for pristine SWCNTs. It is observed that the high density of spin-polarized states are localized in the region of the Fermi level due to the strong interactions between Au (5d orbital) and the adjacent carbon (2p orbital) atoms, which influence the catalytic performance. In addition, we elucidate both the Langmuir-Hinshelwood (LH) and Eley-Rideal (ER) mechanisms of CO oxidation by O 2 . For the LH pathway, the barriers of the rate-limiting step are calculated to be 0.02 eV and 0.05 eV for Au/m-SWCNT and Au/di-SWCNT, respectively. To regenerate the active sites, an ER-like reaction occurs to form a second CO 2 molecule. The ER pathway is observed on Au/m-SWCNT, Au/SW-SWCNT and Au/SWCNT in which the Au/m-SWCNT has a smaller barrier. The comparison with a previous study (Lu et al., J. Phys. Chem. C, 2009, 113, 20156-20160.) indicates that the curvature effect of SWCNTs is important for the catalytic property of the supported single Au. Overall, Au/m-SWCNT is identified as the most active catalyst for CO oxidation compared to pristine SWCNT, SW-SWCNT and di-SWCNT. Our findings give a clear description on the relationship between the defects in the support and the catalytic properties of Au and open a new avenue to develop carbon nanomaterial-based single atom catalysts for application in environmental and energy related fields.

Atomic Force Microscopy Studies on DNA Structural Changes Induced by Vincristine Sulfate and Aspirin

NASA Astrophysics Data System (ADS)

Zhu, Yi; Zeng, Hu; Xie, Jianming; Ba, Long; Gao, Xiang; Lu, Zuhong

2004-04-01

We report that atomic force microscopy (AFM) studies on structural variations of a linear plasmid DNA interact with various concentrations of vincristine sulfate and aspirin. The different binding images show that vincrinstine sulfate binding DNA chains caused some loops and cleavages of the DNA fragments, whereas aspirin interaction caused the width changes and conformational transition of the DNA fragments. Two different DNA structural alternations could be explained by the different mechanisms of the interactions with these two components. Our work indicates that the AFM is a powerful tool in studying the interaction between DNA and small molecules.

Tight-binding model for borophene and borophane

NASA Astrophysics Data System (ADS)

Nakhaee, M.; Ketabi, S. A.; Peeters, F. M.

2018-03-01

Starting from the simplified linear combination of atomic orbitals method in combination with first-principles calculations, we construct a tight-binding (TB) model in the two-centre approximation for borophene and hydrogenated borophene (borophane). The Slater and Koster approach is applied to calculate the TB Hamiltonian of these systems. We obtain expressions for the Hamiltonian and overlap matrix elements between different orbitals for the different atoms and present the SK coefficients in a nonorthogonal basis set. An anisotropic Dirac cone is found in the band structure of borophane. We derive a Dirac low-energy Hamiltonian and compare the Fermi velocities with that of graphene.

Method for producing an atomic oxygen beam

NASA Technical Reports Server (NTRS)

Outlaw, Ronald A. (Inventor)

1989-01-01

A method for producing an atomic oxygen beam is provided by the present invention. First, a material 10' is provided which dissociates molecular oxygen and dissolves atomic oxygen into its bulk. Next, molecular oxygen is exposed to entrance surface 11' of material 10'. Next, material 10' is heated by heater 17' to facilitate the permeation of atomic oxygen through material 10' to the UHV side 12'. UHV side 12' is interfaced with an ultra-high vacuum (UHV) environment provided by UHV pump 15'. The atomic oxygen on the UHV side 12' is excited to a non-binding state by exciter 14' thus producing the release of atomic oxygen to form an atomic oxygen beam 35'.

Effect of dacarbazine on CD44 in live melanoma cells as measured by atomic force microscopy-based nanoscopy.

PubMed

Huang, Xun; He, Jiexiang; Zhang, Huan-Tian; Sun, Kai; Yang, Jie; Wang, Huajun; Zhang, Hongxin; Guo, Zhenzhao; Zha, Zhen-Gang; Zhou, Changren

2017-01-01

CD44 ligand-receptor interactions are known to be involved in regulating cell migration and tumor cell metastasis. High expression levels of CD44 correlate with a poor prognosis of melanoma patients. In order to understand not only the mechanistic basis for dacarbazine (DTIC)-based melanoma treatment but also the reason for the poor prognosis of melanoma patients treated with DTIC, dynamic force spectroscopy was used to structurally map single native CD44-coupled receptors on the surface of melanoma cells. The effect of DTIC treatment was quantified by the dynamic binding strength and the ligand-binding free-energy landscape. The results demonstrated no obvious effect of DTIC on the unbinding force between CD44 ligand and its receptor, even when the CD44 nanodomains were reduced significantly. However, DTIC did perturb the kinetic and thermodynamic interactions of the CD44 ligand-receptor, with a resultant greater dissociation rate, lower affinity, lower binding free energy, and a narrower energy valley for the free-energy landscape. For cells treated with 25 and 75 μg/mL DTIC for 24 hours, the dissociation constant for CD44 increased 9- and 70-fold, respectively. The CD44 ligand binding free energy decreased from 9.94 for untreated cells to 8.65 and 7.39 kcal/mol for DTIC-treated cells, which indicated that the CD44 ligand-receptor complexes on DTIC-treated melanoma cells were less stable than on untreated cells. However, affinity remained in the micromolar range, rather than the millimolar range associated with nonaffinity ligands. Hence, the CD44 receptor could still be activated, resulting in intracellular signaling that could trigger a cellular response. These results demonstrate DTIC perturbs, but not completely inhibits, the binding of CD44 ligand to membrane receptors, suggesting a basis for the poor prognosis associated with DTIC treatment of melanoma. Overall, atomic force microscopy-based nanoscopic methods offer thermodynamic and kinetic insight into the effect of DTIC on the CD44 ligand-binding process.

Effect of dacarbazine on CD44 in live melanoma cells as measured by atomic force microscopy-based nanoscopy

PubMed Central

Huang, Xun; He, Jiexiang; Zhang, Huan-tian; Sun, Kai; Yang, Jie; Wang, Huajun; Zhang, Hongxin; Guo, Zhenzhao; Zha, Zhen-gang; Zhou, Changren

2017-01-01

CD44 ligand–receptor interactions are known to be involved in regulating cell migration and tumor cell metastasis. High expression levels of CD44 correlate with a poor prognosis of melanoma patients. In order to understand not only the mechanistic basis for dacarbazine (DTIC)-based melanoma treatment but also the reason for the poor prognosis of melanoma patients treated with DTIC, dynamic force spectroscopy was used to structurally map single native CD44-coupled receptors on the surface of melanoma cells. The effect of DTIC treatment was quantified by the dynamic binding strength and the ligand-binding free-energy landscape. The results demonstrated no obvious effect of DTIC on the unbinding force between CD44 ligand and its receptor, even when the CD44 nanodomains were reduced significantly. However, DTIC did perturb the kinetic and thermodynamic interactions of the CD44 ligand–receptor, with a resultant greater dissociation rate, lower affinity, lower binding free energy, and a narrower energy valley for the free-energy landscape. For cells treated with 25 and 75 μg/mL DTIC for 24 hours, the dissociation constant for CD44 increased 9- and 70-fold, respectively. The CD44 ligand binding free energy decreased from 9.94 for untreated cells to 8.65 and 7.39 kcal/mol for DTIC-treated cells, which indicated that the CD44 ligand–receptor complexes on DTIC-treated melanoma cells were less stable than on untreated cells. However, affinity remained in the micromolar range, rather than the millimolar range associated with nonaffinity ligands. Hence, the CD44 receptor could still be activated, resulting in intracellular signaling that could trigger a cellular response. These results demonstrate DTIC perturbs, but not completely inhibits, the binding of CD44 ligand to membrane receptors, suggesting a basis for the poor prognosis associated with DTIC treatment of melanoma. Overall, atomic force microscopy-based nanoscopic methods offer thermodynamic and kinetic insight into the effect of DTIC on the CD44 ligand-binding process. PMID:29296081

Atomic Force Microscopy Analysis of the Role of Major DNA-Binding Proteins in Organization of the Nucleoid in Escherichia coli

PubMed Central

Ohniwa, Ryosuke L.; Muchaku, Hiroki; Saito, Shinji; Wada, Chieko; Morikawa, Kazuya

2013-01-01

Bacterial genomic DNA is packed within the nucleoid of the cell along with various proteins and RNAs. We previously showed that the nucleoid in log phase cells consist of fibrous structures with diameters ranging from 30 to 80 nm, and that these structures, upon RNase A treatment, are converted into homogeneous thinner fibers with diameter of 10 nm. In this study, we investigated the role of major DNA-binding proteins in nucleoid organization by analyzing the nucleoid of mutant Escherichia coli strains lacking HU, IHF, H–NS, StpA, Fis, or Hfq using atomic force microscopy. Deletion of particular DNA-binding protein genes altered the nucleoid structure in different ways, but did not release the naked DNA even after the treatment with RNase A. This suggests that major DNA-binding proteins are involved in the formation of higher order structure once 10-nm fiber structure is built up from naked DNA. PMID:23951337

Methylocystis strain SB2 materials and methods

DOEpatents

Semrau, Jeremy D; Gallagher, Warren; Yoon, Sukhwan; Im, Jeongdae; DiSpririto, Alan A; Lee, Sung-Woo; Hartsel, Scott; McEllistrem, Marcus T

2014-01-14

The present disclosures provides isolated or purified compounds, each of which bind to a metal atom. Generally, the compounds are small in size (e.g., molecular weight of less than about 1 kDa) and peptidic in nature, inasmuch as the compounds comprise amino acids. In some embodiments, the compound comprises a structure of Formula I; M.sub.1-P.sub.1-M.sub.2-P.sub.2 wherein each of P.sub.1 and P.sub.2 is a peptide comprising at least two amino acids, M.sub.1 is a first metal binding moiety comprising a substituted imidazolone ring, M.sub.2 is a second metal binding moiety comprising a substituted oxazolone ring, and wherein M.sub.1 and M.sub.2 bind to a single metal atom. Also provided are related complexes, conjugates, cells which synthesize the compounds of the present disclosures, substantially homogenous cultures thereof, kits and compositions, and methods of making or using the materials of the present disclosures.

Prediction of fatty acid-binding residues on protein surfaces with three-dimensional probability distributions of interacting atoms.

PubMed

Mahalingam, Rajasekaran; Peng, Hung-Pin; Yang, An-Suei

2014-08-01

Protein-fatty acid interaction is vital for many cellular processes and understanding this interaction is important for functional annotation as well as drug discovery. In this work, we present a method for predicting the fatty acid (FA)-binding residues by using three-dimensional probability density distributions of interacting atoms of FAs on protein surfaces which are derived from the known protein-FA complex structures. A machine learning algorithm was established to learn the characteristic patterns of the probability density maps specific to the FA-binding sites. The predictor was trained with five-fold cross validation on a non-redundant training set and then evaluated with an independent test set as well as on holo-apo pair's dataset. The results showed good accuracy in predicting the FA-binding residues. Further, the predictor developed in this study is implemented as an online server which is freely accessible at the following website, http://ismblab.genomics.sinica.edu.tw/. Copyright © 2014 Elsevier B.V. All rights reserved.

Molecular dynamics simulation of the interactions between EHD1 EH domain and multiple peptides* #

PubMed Central

Yu, Hua; Wang, Mao-Jun; Xuan, Nan-Xia; Shang, Zhi-Cai; Wu, Jun

2015-01-01

Objective: To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 (EHD1 EH domain) with three peptides containing NPF (asparagine-proline-phenylalanine), DPF (aspartic acid-proline-phenylalanine), and GPF (glycine-proline-phenylalanine) motifs were deciphered at the atomic level. The binding affinities and the underlying structure basis were investigated. Methods: Molecular dynamics (MD) simulations were performed on EHD1 EH domain/peptide complexes for 60 ns using the GROMACS package. The binding free energies were calculated and decomposed by molecular mechanics/generalized Born surface area (MM/GBSA) method using the AMBER package. The alanine scanning was performed to evaluate the binding hot spot residues using FoldX software. Results: The different binding affinities for the three peptides were affected dominantly by van der Waals interactions. Intermolecular hydrogen bonds provide the structural basis of contributions of van der Waals interactions of the flanking residues to the binding. Conclusions: van der Waals interactions should be the main consideration when we design peptide inhibitors of EHD1 EH domain with high affinities. The ability to form intermolecular hydrogen bonds with protein residues can be used as the factor for choosing the flanking residues. PMID:26465136

NMR paves the way for atomic level descriptions of sparsely populated, transiently formed biomolecular conformers.

PubMed

Sekhar, Ashok; Kay, Lewis E

2013-08-06

The importance of dynamics to biomolecular function is becoming increasingly clear. A description of the structure-function relationship must, therefore, include the role of motion, requiring a shift in paradigm from focus on a single static 3D picture to one where a given biomolecule is considered in terms of an ensemble of interconverting conformers, each with potentially diverse activities. In this Perspective, we describe how recent developments in solution NMR spectroscopy facilitate atomic resolution studies of sparsely populated, transiently formed biomolecular conformations that exchange with the native state. Examples of how this methodology is applied to protein folding and misfolding, ligand binding, and molecular recognition are provided as a means of illustrating both the power of the new techniques and the significant roles that conformationally excited protein states play in biology.

Protein Structure and Function Prediction Using I-TASSER

PubMed Central

Yang, Jianyi; Zhang, Yang

2016-01-01

I-TASSER is a hierarchical protocol for automated protein structure prediction and structure-based function annotation. Starting from the amino acid sequence of target proteins, I-TASSER first generates full-length atomic structural models from multiple threading alignments and iterative structural assembly simulations followed by atomic-level structure refinement. The biological functions of the protein, including ligand-binding sites, enzyme commission number, and gene ontology terms, are then inferred from known protein function databases based on sequence and structure profile comparisons. I-TASSER is freely available as both an on-line server and a stand-alone package. This unit describes how to use the I-TASSER protocol to generate structure and function prediction and how to interpret the prediction results, as well as alternative approaches for further improving the I-TASSER modeling quality for distant-homologous and multi-domain protein targets. PMID:26678386

Shape information from a critical point analysis of calculated electron density maps: application to DNA-drug systems

NASA Astrophysics Data System (ADS)

Leherte, L.; Allen, F. H.; Vercauteren, D. P.

1995-04-01

A computational method is described for mapping the volume within the DNA double helix accessible to a groove-binding antibiotic, netropsin. Topological critical point analysis is used to locate maxima in electron density maps reconstructed from crystallographically determined atomic coordinates. The peaks obtained in this way are represented as ellipsoids with axes related to local curvature of the electron density function. Combining the ellipsoids produces a single electron density function which can be probed to estimate effective volumes of the interacting species. Close complementarity between host and ligand in this example shows the method to be a good representation of the electron density function at various resolutions; while at the atomic level the ellipsoid method gives results which are in close agreement with those from the conventional, spherical, van der Waals approach.

Shape information from a critical point analysis of calculated electron density maps: Application to DNA-drug systems

NASA Astrophysics Data System (ADS)

Leherte, Laurence; Allen, Frank H.

1994-06-01

A computational method is described for mapping the volume within the DNA double helix accessible to the groove-binding antibiotic netropsin. Topological critical point analysis is used to locate maxima in electron density maps reconstructed from crystallographically determined atomic coordinates. The peaks obtained in this way are represented as ellipsoids with axes related to local curvature of the electron density function. Combining the ellipsoids produces a single electron density function which can be probed to estimate effective volumes of the interacting species. Close complementarity between host and ligand in this example shows the method to give a good representation of the electron density function at various resolutions. At the atomic level, the ellipsoid method gives results which are in close agreement with those from the conventional spherical van der Waals approach.

Molecular Dynamics Simulations to Determine the Structure and Dynamics of Hepatitis B Virus Capsid Bound to a Novel Anti-viral Drug.

PubMed

Watanabe, Go; Sato, Shunsuke; Iwadate, Mitsuo; Umeyama, Hideaki; Hayakawa, Michiyo; Murakami, Yoshiki; Yoneda, Shigetaka

2016-01-01

Hepatitis B virus (HBV) chronically infects millions of people worldwide and is a major cause of serious liver diseases, including liver cirrhosis and liver cancer. In our previous study, in silico screening was used to isolate new anti-viral compounds predicted to bind to the HBV capsid. Four of the isolated compounds have been reported to suppress the cellular multiplication of HBV experimentally. In the present study, molecular dynamics simulations of the HBV capsid were performed under rotational symmetry boundary conditions, to clarify how the structure and dynamics of the capsid are affected at the atomic level by the binding of one of the isolated compounds, C13. Two simulations of the free HBV capsid, two further simulations of the capsid-C13 complex, and one simulation of the capsid-AT-130 complex were performed. For statistical confidence, each set of simulations was repeated by five times, changing the simulation conditions. C13 continued to bind at the predicted binding site during the simulations, supporting the hypothesis that C13 is a capsid-binding compound. The structure and dynamics of the HBV capsid were greatly influenced by the binding and release of C13, and these effects were essentially identical to those seen for AT-130, indicating that C13 likely inhibits the function of the HBV capsid.

In vitro and in silico assessment of the structure-dependent binding of bisphenol analogues to glucocorticoid receptor.

PubMed

Zhang, Jie; Zhang, Tiehua; Guan, Tianzhu; Yu, Hansong; Li, Tiezhu

2017-03-01

Widespread use of bisphenol A (BPA) and other bisphenol analogues has attracted increasing attention for their potential adverse effects. As environmental endocrine-disrupting compounds (EDCs), bisphenols (BPs) may activate a variety of nuclear receptors, including glucocorticoid receptor (GR). In this work, the binding of 11 BPs to GR was investigated by fluorescence polarization (FP) assay in combination with molecular dynamics simulations. The human glucocorticoid receptor was prepared as a soluble recombinant protein. A fluorescein-labeled dexamethasone derivative (Dex-fl) was employed as tracer. Competitive displacement of Dex-fl from GR by BPs showed that the binding affinities of bisphenol analogues were largely dependent on their characteristic functional groups. In order to further understand the relationship between BPs structures and their GR-mediated activities, molecular docking was utilized to explore the binding modes at the atomic level. The results confirmed that structural variations of bisphenol analogues contributed to different interactions of BPs with GR, potentially causing distinct toxic effects. Comparison of the calculated binding energies vs. experimental binding affinities yielded a good correlation (R 2  = 0.8266), which might be helpful for the design of environmentally benign materials with reduced toxicities. In addition, the established FP assay based on GR exhibited the potential to offer an alternative to traditional methods for the detection of bisphenols.

Comparative in vitro biocompatibility of nickel-titanium, pure nickel, pure titanium, and stainless steel: genotoxicity and atomic absorption evaluation.

PubMed

Assad, M; Lemieux, N; Rivard, C H; Yahia, L H

1999-01-01

The genotoxicity level of nickel-titanium (NiTi) was compared to that of its pure constituents, pure nickel (Ni) and pure titanium (Ti) powders, and also to 316L stainless steel (316L SS) as clinical reference material. In order to do so, a dynamic in vitro semiphysiological extraction was performed with all metals using agitation and ISO requirements. Peripheral blood lymphocytes were then cultured in the presence of all material extracts, and their comparative genotoxicity levels were assessed using electron microscopy-in situ end-labeling (EM-ISEL) coupled to immunogold staining. Cellular chromatin exposition to pure Ni and 316L SS demonstrated a significantly stronger gold binding than exposition to NiTi, pure Ti, or the untreated control. In parallel, graphite furnace atomic absorption spectrophotometry (AAS) was also performed on all extraction media. The release of Ni atoms took the following decreasing distribution for the different resulting semiphysiological solutions: pure Ni, 316L SS, NiTi, Ti, and controls. Ti elements were detected after elution of pure titanium only. Both pure titanium and nickel-titanium specimens obtained a relative in vitro biocompatibility. Therefore, this quantitative in vitro study provides optimistic results for the eventual use of nickel-titanium alloys as surgical implant materials.

Simulation of Quantum Phenomena in Nanowire Sensors

DTIC Science & Technology

2014-12-17

Ag and Pt atoms: search for nanocatalysts, Journal of Physics B: Atomic, Molecular and Optical Physics, (07 2011): 0. doi: 10.1088/0953- 4075/44...International Advisory Committee, African Laser Centre Annual Workshop 3-5 Nov. 2014, Moroccan Foundation for Advanced Science, Innovation & Research...atoms encapsulated inside C180 and C240 we found: 1) The Xe-C180 and Xe-C240 binding energies along some high symmetry directions showed the

Tunable reactivity of supported single metal atoms by impurity engineering of the MgO(001) support.

PubMed

Pašti, Igor A; Johansson, Börje; Skorodumova, Natalia V

2018-02-28

Development of novel materials may often require a rational use of high price components, like noble metals, in combination with the possibility to tune their properties in a desirable way. Here we present a theoretical DFT study of Au and Pd single atoms supported by doped MgO(001). By introducing B, C and N impurities into the MgO(001) surface, the interaction between the surface and the supported metal adatoms can be adjusted. Impurity atoms act as strong binding sites for Au and Pd adatoms and can help to produce highly dispersed metal particles. The reactivity of metal atoms supported by doped MgO(001), as probed by CO, is altered compared to their counterparts on pristine MgO(001). We find that Pd atoms on doped MgO(001) are less reactive than on perfect MgO(001). In contrast, Au adatoms bind CO much more strongly when placed on doped MgO(001). In the case of Au on N-doped MgO(001) we find that charge redistribution between the metal atom and impurity takes place even when not in direct contact, which enhances the interaction of Au with CO. The presented results suggest possible ways for optimizing the reactivity of oxide supported metal catalysts through impurity engineering.

Structural stability and O{sub 2} dissociation on nitrogen-doped graphene with transition metal atoms embedded: A first-principles study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Mingye; Wang, Lu, E-mail: lwang22@suda.edu.cn, E-mail: yyli@suda.edu.cn; Li, Min

2015-06-15

By using first-principles calculations, we investigate the structural stability of nitrogen-doped (N-doped) graphene with graphitic-N, pyridinic-N and pyrrolic-N, and the transition metal (TM) atoms embedded into N-doped graphene. The structures and energetics of TM atoms from Sc to Ni embedded into N-doped graphene are studied. The TM atoms at N{sub 4}V {sub 2} forming a 4N-centered structure shows the strongest binding and the binding energies are more than 7 eV. Finally, we investigate the catalytic performance of N-doped graphene with and without TM embedding for O{sub 2} dissociation, which is a fundamental reaction in fuel cells. Compared to the pyridinic-N,more » the graphitic-N is more favorable to dissociate O{sub 2} molecules with a relatively low reaction barrier of 1.15 eV. However, the catalytic performance on pyridinic-N doped structure can be greatly improved by embedding TM atoms, and the energy barrier can be reduced to 0.61 eV with V atom embedded. Our results provide the stable structure of N-doped graphene and its potential applications in the oxygen reduction reactions.« less

Tailoring oxide properties: An impact on adsorption characteristics of molecules and metals

NASA Astrophysics Data System (ADS)

Honkala, Karoliina

2014-12-01

Both density functional theory calculations and numerous experimental studies demonstrate a variety of unique features in metal supported oxide films and transition metal doped simple oxides, which are markedly different from their unmodified counterparts. This review highlights, from the computational perspective, recent literature on the properties of the above mentioned surfaces and how they adsorb and activate different species, support metal aggregates, and even catalyse reactions. The adsorption of Au atoms and clusters on metal-supported MgO films are reviewed together with the cluster's theoretically predicted ability to activate and dissociate O2 at the Au-MgO(100)/Ag(100) interface, as well as the impact of an interface vacancy to the binding of an Au atom. In contrast to a bulk MgO surface, an Au atom binds strongly on a metal-supported ultra-thin MgO film and becomes negatively charged. Similarly, Au clusters bind strongly on a supported MgO(100) film and are negatively charged favouring 2D planar structures. The adsorption of other metal atoms is briefly considered and compared to that of Au. Existing computational literature of adsorption and reactivity of simple molecules including O2, CO, NO2, and H2O on mainly metal-supported MgO(100) films is discussed. Chemical reactions such as CO oxidation and O2 dissociation are discussed on the bare thin MgO film and on selected Au clusters supported on MgO(100)/metal surfaces. The Au atoms at the perimeter of the cluster are responsible for catalytic activity and calculations predict that they facilitate dissociative adsorption of oxygen even at ambient conditions. The interaction of H2O with a flat and stepped Ag-supported MgO film is summarized and compared to bulk MgO. The computational results highlight spontaneous dissociation on MgO steps. Furthermore, the impact of water coverage on adsorption and dissociation is addressed. The modifications, such as oxygen vacancies and dopants, at the oxide-metal interface and their effect on the adsorption characteristics of water and Au are summarized. Finally, more limited computational literature on transition metal (TM) doped CaO(100) and MgO(100) surfaces is presented. Again, Au is used as a probe species. Similar to metal-supported MgO films, Au binds more strongly than on undoped CaO(100) and becomes negatively charged. The discussion focuses on rationalization of Au adsorption with the help of Born-Haber cycle, which reveals that the so-called redox energy including the electron transfer from the dopant to the Au atom together with the simultaneous structural relaxation of lattice atoms is responsible for enhanced binding. In addition, adsorption energy dependence on the position and type of the dopant is summarized.

Atoms and Molecules Interacting with Light

NASA Astrophysics Data System (ADS)

van der Straten, Peter; Metcalf, Harold

2016-02-01

Part I. Atom-Light Interaction: 1. The classical physics pathway; Appendix 1.A. Damping force on an accelerating charge; Appendix 1.B. Hanle effect; Appendix 1.C. Optical tweezers; 2. Interaction of two-level atoms and light; Appendix 2.A. Pauli matrices for motion of the bloch vector; Appendix 2.B. The Ramsey method; Appendix 2.C. Echoes and interferometry; Appendix 2.D. Adiabatic rapid passage; Appendix 2.E Superposition and entanglement; 3. The atom-light interaction; Appendix 3.A. Proof of the oscillator strength theorem; Appendix 3.B. Electromagnetic fields; Appendix 3.C. The dipole approximation; Appendix 3.D. Time resolved fluorescence from multi-level atoms; 4. 'Forbidden' transitions; Appendix 4.A. Higher order approximations; 5. Spontaneous emission; Appendix 5.A. The quantum mechanical harmonic oscillator; Appendix 5.B. Field quantization; Appendix 5.C. Alternative theories to QED; 6. The density matrix; Appendix 6.A. The Liouville-von Neumann equation; Part II. Internal Structure: 7. The hydrogen atom; Appendix 7.A. Center-of-mass motion; Appendix 7.B. Coordinate systems; Appendix 7.C. Commuting operators; Appendix 7.D. Matrix elements of the radial wavefunctions; 8. Fine structure; Appendix 8.A. The Sommerfeld fine-structure constant; Appendix 8.B. Measurements of the fine structure 9. Effects of the nucleus; Appendix 9.A. Interacting magnetic dipoles; Appendix 9.B. Hyperfine structure for two spin =2 particles; Appendix 9.C. The hydrogen maser; 10. The alkali-metal atoms; Appendix 10.A. Quantum defects for the alkalis; Appendix 10.B. Numerov method; 11. Atoms in magnetic fields; Appendix 11.A. The ground state of atomic hydrogen; Appendix 11.B. Positronium; Appendix 11.C. The non-crossing theorem; Appendix 11.D. Passage through an anticrossing: Landau-Zener transitions; 12. Atoms in electric fields; 13. Rydberg atoms; 14. The helium atom; Appendix 14.A. Variational calculations; Appendix 14.B. Detail on the variational calculations of the ground state; 15. The periodic system of the elements; Appendix 15. A paramagnetism; Appendix 15.B. The color of gold; 16. Molecules; Appendix 16.A. Morse potential; 17. Binding in the hydrogen molecule; Appendix 17.A. Confocal elliptical coordinates; Appendix 17.B. One-electron two-center integrals; Appendix 17.C. Electron-electron interaction in molecular hydrogen; 18. Ultra-cold chemistry; Part III. Applications: 19. Optical forces and laser cooling; 20. Confinement of neutral atoms; 21. Bose-Einstein condensation; Appendix 21.A. Distribution functions; Appendix 21.B. Density of states; 22. Cold molecules; 23. Three level systems; Appendix 23.A. General Case for _1 , _2; 24. Fundamental physics; Part IV. Appendices: Appendix A. Notation and definitions; Appendix B. Units and notation; Appendix C. Angular momentum in quantum mechanics; Appendix D. Transition strengths; References; Index.

Characterisation of zinc-binding domains of peroxisomal RING finger proteins using size exclusion chromatography/inductively coupled plasma-mass spectrometry.

PubMed

Koellensperger, Gunda; Daubert, Simon; Erdmann, Ralf; Hann, Stephan; Rottensteiner, Hanspeter

2007-11-01

We determined the zinc binding stoichiometry of peroxisomal RING finger proteins by measuring sulfur/metal ratios using inductively coupled plasma-mass spectrometry coupled to size exclusion chromatography, a strategy that provides a fast and quantitative overview on the binding of metals in proteins. As a quality control, liquid chromatography-electrospray ionisation-time of flight-mass spectrometry was used to measure the molar masses of the intact proteins. The RING fingers of Pex2p, Pex10p, and Pex12p showed a stoichiometry of 2.0, 2.1, and 1.2 mol zinc/mol protein, respectively. Thus, Pex2p and Pex10p possess a typical RING domain with two coordinated zinc atoms, whereas that of Pex12p coordinates only a single zinc atom.

Intermolecular symmetry-adapted perturbation theory study of large organic complexes.

PubMed

Heßelmann, Andreas; Korona, Tatiana

2014-09-07

Binding energies for the complexes of the S12L database by Grimme [Chem. Eur. J. 18, 9955 (2012)] were calculated using intermolecular symmetry-adapted perturbation theory combined with a density-functional theory description of the interacting molecules. The individual interaction energy decompositions revealed no particular change in the stabilisation pattern as compared to smaller dimer systems at equilibrium structures. This demonstrates that, to some extent, the qualitative description of the interaction of small dimer systems may be extrapolated to larger systems, a method that is widely used in force-fields in which the total interaction energy is decomposed into atom-atom contributions. A comparison of the binding energies with accurate experimental reference values from Grimme, the latter including thermodynamic corrections from semiempirical calculations, has shown a fairly good agreement to within the error range of the reference binding energies.

Dihydroxo-bridged dimeric Cu(II) system containing sandwiched non-coordinating phenylacetate anion: Crystal structure, spectroscopic, anti-bacterial, anti-fungal and DNA-binding studies of [(phen)(H2O)Cu(OH)2Cu(H2O)(phen)]2L.6H2O: (HL = phenylacetic acid; phen = 1,10-phenanthroline)

NASA Astrophysics Data System (ADS)

Iqbal, Muhammad; Ali, Saqib; Tahir, Muhammad Nawaz; Shah, Naseer Ali

2017-09-01

This paper reports the synthesis, X-ray crystal structure, DNA-binding, antibacterial and antifungal studies of a rare dihydroxo-bridged dinuclear copper(II) complex including 1,10-phenanthroline (Phen) ligands and phenylacetate (L) anions, [Cu2(Phen)2(OH)2(H2O)2].2L.6H2O. Structural data revealed distorted square-pyramidal geometry for each copper(II) atom with the basal plane formed by the two nitrogen atoms of the phenantroline ligand and the oxygen atoms of two bridging hydroxyl groups. The apical positions are filled by the oxygen atom from a water molecule. This forms a centrosymmetric cationic dimer where the uncoordinated phenylacetate ligands serve to balance the electrical charge. The dimers interact by means of hydrogen bonds aided by the coordinated as well as uncoordinated water molecules and phenyl-acetate moieties in the crystal lattice. The binding ability of the complex with salmon sperm DNA was determined using cyclic voltammetry and absorption spectroscopy yielding binding constants 2.426 × 104 M-1 and 1.399 × 104 M-1, respectively. The complex was screened against two Gram-positive (Micrococcus luteus and Bacillus subtilis) and one Gram-negative (Escherichia coli) bacterial strains exhibiting significant activity against all the three strains. The complex exhibited significant, moderate and no activity against fungal strains Mucor piriformis, Helminthosporium solani and Aspergillus Niger, respectively. These preliminary tests indicate the competence of the complex towards the development of a potent biological drug.

A Specific Peptide with Calcium-Binding Capacity from Defatted Schizochytrium sp. Protein Hydrolysates and the Molecular Properties.

PubMed

Cai, Xixi; Yang, Qian; Lin, Jiaping; Fu, Nanyan; Wang, Shaoyun

2017-03-29

Marine microorganisms have been proposed as a new kind of protein source. Efforts are needed in order to transform the protein-rich biological wastes left after lipid extraction into value-added bio-products. Thus, the utilization of protein recovered from defatted Schizochytrium sp. by-products presents an opportunity. A specific peptide Tyr-Leu (YL) with calcium-binding capacity was purified from defatted Schizochytrium sp. protein hydrolysates through gel filtration chromatography and RP-HPLC. The calcium-binding activity of YL reached 126.34 ± 3.40 μg/mg. The calcium-binding mechanism was investigated through ultraviolet, fluorescence and infrared spectroscopy. The results showed that calcium ions could form dative bonds with carboxyl oxygen atoms and amino nitrogen atoms as well as the nitrogen and oxygen atoms of amide bonds. YL-Ca exhibited excellent thermal stability and solubility, which was beneficial for its absorption and transport in the basic intestinal tract of the human body. Moreover, the cellular uptake of calcium in Caco-2 cells showed that YL-Ca could enhance calcium uptake efficiency and protect calcium ions against precipitation caused by dietary inhibitors such as tannic acid, oxalate, phytate and metal ions. The findings indicate that the by-product of Schizochytrium sp. is a promising source for making peptide-calcium bio-products as algae-based functional supplements for human beings.

Virtual screening of integrase inhibitors by large scale binding free energy calculations: the SAMPL4 challenge

PubMed Central

Gallicchio, Emilio; Deng, Nanjie; He, Peng; Wickstrom, Lauren; Perryman, Alexander L.; Santiago, Daniel N.; Forli, Stefano; Olson, Arthur J.; Levy, Ronald M.

2014-01-01

As part of the SAMPL4 blind challenge, filtered AutoDock Vina ligand docking predictions and large scale binding energy distribution analysis method binding free energy calculations have been applied to the virtual screening of a focused library of candidate binders to the LEDGF site of the HIV integrase protein. The computational protocol leveraged docking and high level atomistic models to improve enrichment. The enrichment factor of our blind predictions ranked best among all of the computational submissions, and second best overall. This work represents to our knowledge the first example of the application of an all-atom physics-based binding free energy model to large scale virtual screening. A total of 285 parallel Hamiltonian replica exchange molecular dynamics absolute protein-ligand binding free energy simulations were conducted starting from docked poses. The setup of the simulations was fully automated, calculations were distributed on multiple computing resources and were completed in a 6-weeks period. The accuracy of the docked poses and the inclusion of intramolecular strain and entropic losses in the binding free energy estimates were the major factors behind the success of the method. Lack of sufficient time and computing resources to investigate additional protonation states of the ligands was a major cause of mispredictions. The experiment demonstrated the applicability of binding free energy modeling to improve hit rates in challenging virtual screening of focused ligand libraries during lead optimization. PMID:24504704

Atomic and molecular adsorption on Fe(110)

DOE PAGES

Xu, Lang; Kirvassilis, Demetrios; Bai, Yunhai; ...

2017-09-12

Iron is the principal catalyst for the ammonia synthesis process and the Fischer–Tropsch process, as well as many other heterogeneously catalyzed reactions. It is thus of fundamental importance to understand the interactions between the iron surface and various reaction intermediates. Here in this paper, we present a systematic study of atomic and molecular adsorption behavior over Fe(110) using periodic, self-consistent density functional theory (DFT-GGA) calculations. The preferred binding sites, binding energies, and the corresponding surface deformation energies of five atomic species (H, C, N, O, and S), six molecular species (NH 3, CH 4, N 2, CO, HCN, and NO),more » and eleven molecular fragments (CH, CH 2, CH 3, NH, NH 2, OH, CN, COH, HCO, NOH, and HNO) were determined on the Fe(110) surface at a coverage of 0.25 monolayer. The binding strengths calculated using the PW91 functional decreased in the following order: C> CH > N > O > S > NH > COH > CN > CH2 > NOH > OH > HNO > HCO > NH2 > H > NO > HCN > CH 3 > CO > N 2 > NH 3. No stable binding structures were observed for CH 4. The estimated diffusion barriers and pathways, as well as the adsorbate-surface and intramolecular vibrational modes of all the adsorbates at their preferred binding sites, were identified. Using the calculated adsorption energetics, we constructed the potential energy surfaces for a few surface reactions including the decomposition of methane, ammonia, dinitrogen, carbon monoxide, and nitric oxide. These potential energy surfaces provide valuable insight into the ability of Fe(110) to catalyze common elementary steps.« less

Modelling free and oxide-supported nanoalloy catalysts: comparison of bulk-immiscible Pd-Ir and Au-Rh systems and influence of a TiO2 support.

PubMed

Demiroglu, Ilker; Fan, Tian-E; Li, Z Y; Yuan, Jun; Liu, Tun-Dong; Piccolo, Laurent; Johnston, Roy L

2018-05-24

The relative stabilities of different chemical arrangements of Pd-Ir and Au-Rh nanoalloys (and their pure metal equivalents) are studied, for a range of compositions, for fcc truncated octahedral 38- and 79-atom nanoparticles (NPs). For the 38-atom NPs, comparisons are made of pure and alloy NPs supported on a TiO2(110) slab. The relative energies of different chemical arrangements are found to be similar for Pd-Ir and Au-Rh nanoalloys, and depend on the cohesive and surface energies of the component metals. For supported nanoalloys on TiO2, the interaction with the surface is greater for Ir (Rh) than Pd (Au): most of the pure NPs and nanoalloys preferentially bind to the TiO2 surface in an edge-on configuration. When Au-Rh nanoalloys are bound to the surface through Au, the surface binding strength is lower than for the pure Au NP, while the Pd-surface interaction is found to be greater for Pd-Ir nanoalloys than for the pure Pd NP. However, alloying leads to very little difference in Ir-surface and Rh-surface binding strength. Comparing the relative stabilities of the TiO2-supported NPs, the results for Pd-Ir and Au-Rh nanoalloys are the same: supported Janus NPs, whose Ir (Rh) atoms bind to the TiO2 surface, bind most strongly to the surface, becoming closer in energy to the core-shell configurations (Ir@Pd and Rh@Au) which are favoured for the free particles.

Comparison of mechanistic transport cycle models of ABC exporters.

PubMed

Szöllősi, Dániel; Rose-Sperling, Dania; Hellmich, Ute A; Stockner, Thomas

2018-04-01

ABC (ATP binding cassette) transporters, ubiquitous in all kingdoms of life, carry out essential substrate transport reactions across cell membranes. Their transmembrane domains bind and translocate substrates and are connected to a pair of nucleotide binding domains, which bind and hydrolyze ATP to energize import or export of substrates. Over four decades of investigations into ABC transporters have revealed numerous details from atomic-level structural insights to their functional and physiological roles. Despite all these advances, a comprehensive understanding of the mechanistic principles of ABC transporter function remains elusive. The human multidrug resistance transporter ABCB1, also referred to as P-glycoprotein (P-gp), is one of the most intensively studied ABC exporters. Using ABCB1 as the reference point, we aim to compare the dominating mechanistic models of substrate transport and ATP hydrolysis for ABC exporters and to highlight the experimental and computational evidence in their support. In particular, we point out in silico studies that enhance and complement available biochemical data. "This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain." Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Systematic study of imidazoles inhibiting IDO1 via the integration of molecular mechanics and quantum mechanics calculations.

PubMed

Zou, Yi; Wang, Fang; Wang, Yan; Guo, Wenjie; Zhang, Yihua; Xu, Qiang; Lai, Yisheng

2017-05-05

Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as an attractive target for cancer immunotherapy. To rationalize the detailed interactions between IDO1 and its inhibitors at the atomic level, an integrated computational approach by combining molecular mechanics and quantum mechanics methods was employed in this report. Specifically, the binding modes of 20 inhibitors was initially investigated using the induced fit docking (IFD) protocol, which outperformed other two docking protocols in terms of correctly predicting ligand conformations. Secondly, molecular dynamics (MD) simulations and MM/PBSA free energy calculations were employed to determine the dynamic binding process and crucial residues were confirmed through close contact analysis, hydrogen-bond analysis and binding free energy decomposition calculations. Subsequent quantum mechanics and nonbonding interaction analysis were carried out to provide in-depth explanations on the critical role of those key residues, and Arg231 and 7-propionate of the heme group were major contributors to ligand binding, which lowed a great amount of interaction energy. We anticipate that these findings will be valuable for enzymatic studies and rational drug design. Copyright © 2017. Published by Elsevier Masson SAS.

Pd n Ag (4-n) and Pd n Pt (4-n) clusters on MgO (100): a density functional surface genetic algorithm investigation

DOE PAGES

Heard, Christopher J.; Heiles, Sven; Vajda, Stefan; ...

2014-08-07

We employed the novel surface mode of the Birmingham Cluster Genetic Algorithm (S-BCGA) for the global optimisation of noble metal tetramers upon an MgO(100) substrate at the GGA-DFT level of theory. The effect of element identity and alloying in surface-bound neutral subnanometre clusters is determined by energetic comparison between all compositions of Pd nAg (4-n) and Pd nPt (4-n). And while the binding strengths to the surface increase in the order Pt > Pd > Ag, the excess energy profiles suggest a preference for mixed clusters for both cases. The binding of CO is also modelled, showing that the adsorptionmore » site can be predicted solely by electrophilicity. Comparison to CO binding on a single metal atom shows a reversal of the 5s-d activation process for clusters, weakening the cluster surface interaction on CO adsorption. Charge localisation determines homotop, CO binding and surface site preferences. Furthermore, the electronic behaviour, which is intermediate between molecular and metallic particles allows for tunable features in the subnanometre size range.« less

Conductance of three-terminal molecular bridge based on tight-binding theory

NASA Astrophysics Data System (ADS)

Wang, Li-Guang; Li, Yong; Yu, Ding-Wen; Katsunori, Tagami; Masaru, Tsukada

2005-05-01

The quantum transmission characteristic of three-benzene ring nano-molecular bridge is investigated theoretically by using Green's function approach based on tight-binding theory with only a π orbital per carbon atom at the site. The transmission probabilities that electrons transport through the molecular bridge from one terminal to the other two terminals are obtained. The electronic current distributions inside the molecular bridge are calculated and shown in graphical analogy by the current density method based on Fisher-Lee formula at the energy points E = ±0.42, ±1.06 and ±1.5, respectively, where the transmission spectra appear peaks. We find that the transmission spectra are related to the incident electronic energy and the molecular levels strongly and the current distributions agree well with Kirchhoff quantum current momentum conservation law.

Detailed mechanism of squalene epoxidase inhibition by terbinafine.

PubMed

Nowosielski, Marcin; Hoffmann, Marcin; Wyrwicz, Lucjan S; Stepniak, Piotr; Plewczynski, Dariusz M; Lazniewski, Michal; Ginalski, Krzysztof; Rychlewski, Leszek

2011-02-28

Squalene epoxidase (SE) is a key flavin adenine dinucleotide (FAD)-dependent enzyme of ergosterol and cholesterol biosynthetic pathways and an attractive potential target for drugs used to inhibit the growth of pathogenic fungi or to lower cholesterol level. Although many studies on allylamine drugs activity have been published during the last 30 years, up until now no detailed mechanism of the squalene epoxidase inhibition has been presented. Our study brings such a model at atomic resolution in the case of yeast Saccharomyces cerevisiae . Presented data resulting from modeling studies are in excellent agreement with experimental findings. A fully atomic three-dimensional (3D) model of squalene epoxidase (EC 1.14.99.7) from S. cerevisiae was built with the help of 3D-Jury approach and further screened based on data known from mutation experiments leading to terbinafine resistance. Docking studies followed by molecular dynamics simulations and quantum interaction energy calculations [MP2/6-31G(d)] resulted in the identification of the terbinafine-squalene epoxidase mode of interaction. In the energetically most likely orientation of terbinafine its interaction energy with the protein is ca. 120 kJ/mol. In the favorable position the terbinafine lipophilic moiety is located vertically inside the squalene epoxidase binding pocket with the tert-butyl group oriented toward its center. Such a position results in the SE conformational changes and prevents the natural substrate from being able to bind to the enzyme's active site. That would explain the noncompetitive manner of SE inhibition. We found that the strongest interaction between terbinafine and SE stems from hydrogen bonding between hydrogen-bond donors, hydroxyl group of Tyr90 and amine nitrogen atom of terbinafine. Moreover, strong attractive interactions were recorded for amino acids whose mutations resulted in terbinafine resistance. Our results, elucidating at a molecular level the mode of terbinafine inhibitory activity, can be utilized in designing more potent or selective antifungal drugs or even medicines lowering cholesterol in humans.

ATOMIC PHYSICS, AN AUTOINSTRUCTIONAL PROGRAM, VOLUME 3, SUPPLEMENT.

ERIC Educational Resources Information Center

DETERLINE, WILLIAM A.; KLAUS, DAVID J.

THE AUTOINSTRUCTIONAL MATERIALS IN THIS TEXT WERE PREPARED FOR USE IN AN EXPERIMENTAL STUDY, OFFERING SELF-TUTORING MATERIAL FOR LEARNING ATOMIC PHYSICS. THE TOPICS COVERED ARE (1) NUCLEAR BINDING ENERGY, (2) DISCOVERY OF RADIOACTIVITY, (3) RADIOACTIVE RADIATIONS, (4) ALPHA AND BETA DECAY, (5) BETA DECAY REACTIONS, (6) RADIOACTIVE DATING AND…

Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.

PubMed

Schnute, Mark E; O'Brien, Patrick M; Nahra, Joe; Morris, Mark; Howard Roark, W; Hanau, Cathleen E; Ruminski, Peter G; Scholten, Jeffrey A; Fletcher, Theresa R; Hamper, Bruce C; Carroll, Jeffery N; Patt, William C; Shieh, Huey S; Collins, Brandon; Pavlovsky, Alexander G; Palmquist, Katherine E; Aston, Karl W; Hitchcock, Jeffrey; Rogers, Michael D; McDonald, Joseph; Johnson, Adam R; Munie, Grace E; Wittwer, Arthur J; Man, Chiu-Fai; Settle, Steven L; Nemirovskiy, Olga; Vickery, Lillian E; Agawal, Arun; Dyer, Richard D; Sunyer, Teresa

2010-01-15

Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model. Copyright 2009 Elsevier Ltd. All rights reserved.

Energetics of a Li Atom adsorbed on B/N doped graphene with monovacancy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rani, Babita, E-mail: babitabaghla15@gmail.com; Department of Physics, Punjabi University, Patiala 147002; Jindal, V.K.

We use density functional theory (DFT) to study the adsorption properties and diffusion of Li atom across B/N-pyridinic graphene. Regardless of the dopant type, B atoms of B-pyridinic graphene lose electron density. On the other hand, N atoms (p-type dopants) have tendency to gain electron density in N-pyridinic graphene. Higher chemical reactivity and electronic conductivity of B/N-pyridinic graphene are responsible for stronger binding of Li with the substrates as compared to pristine graphene. The binding energy of Li with B/N-pyridinic graphene exceeds the cohesive energy of bulk Li, making it energetically unfavourable for Li to form clusters on these substrates.more » Li atom gets better adsorbed on N-pyridinic graphene due to an additional p-p hybridization of the orbitals while Li on B-pyridinic prefers the ionic bonding. Also, significant distortion of N-pyridinic graphene upon Li adsorption is a consequence of the change in bonding mechanism between Li atom and the substrate. Our results show that bonding character and hence binding energies between Li and graphene can be tuned with the help of B/N doping of monovacancy defects. Further, the sites for most stable adsorption are different for the two types of doped and defective graphene, leading to greater Li uptake capacity of B-pyridinic graphene near the defect. In addition, B-pyridinic graphene offering lower diffusion barrier, ensures better Li kinetics. Thus, B-pyridinic graphene presents itself as a better anode material for LIBs as compared to N-pyridinic graphene. - Graphical abstract: Adsorption and diffusion of Li atom across the B/N doped monovacancy graphene is studied using ab-initio DFT calculations. Our results show that bonding mechanism and binding of Li with graphene can be tuned with the help of N/B doping of defects. Also, B-pyridinic graphene presents itself as a better anode material for lithium ion batteries as compared to N-pyridinic graphene. Display Omitted - Highlights: • Density functional theory (DFT) calculations are employed to study the effect of B/N doping of monovacancy graphene on the adsorption and diffusion of Li atom across the sheet using VASP. • Higher chemical reactivity and electronic conductivity of B/N-pyridinic graphene (p-type semiconductors) as compared to pristine graphene lead to stronger binding of Li. It also exceeds the cohesive energy of bulk Li. Thus, uniform distribution of Li atoms is possible on both substrates. • Li gets adsorbed stably at centre of defect in N-pyridinic graphene. B-pyridinic graphene has stable adsorption of Li at hollow site of hexagon, neighboring the defect, having only one boron atom. It leads to maximum Li uptake capacity of B-pyridinic graphene. • Li gets better adsorbed on N-pyridinic graphene due to an additional p-p hybridization of the orbitals. This change in bonding mechanism causes significant distortion of the substrate. On the other hand, Li on B-pyridinic graphene shows ionic bonding character. • B-pyridinic graphene offers lower energy barrier for Li to diffuse across the substrate in comparison to N-pyridinic graphene. Thus, B-pyridinic graphene presents itself as a better anode material for lithium ion batteries due to optimal Li adsorption and better diffusion kinetics.« less

Single Molecule Science for Personalized Nanomedicine: Atomic Force Microscopy of Biopolymer-Protein Interactions

NASA Astrophysics Data System (ADS)

Hsueh, Carlin

Nanotechnology has a unique and relatively untapped utility in the fields of medicine and dentistry at the level of single-biopolymer and -molecule diagnostics. In recent years atomic force microscopy (AFM) has garnered much interest due to its ability to obtain atomic-resolution of molecular structures and probe biophysical behaviors of biopolymers and proteins in a variety of biologically significant environments. The work presented in this thesis focuses on the nanoscale manipulation and observation of biopolymers to develop an innovative technology for personalized medicine while understanding complex biological systems. These studies described here primarily use AFM to observe biopolymer interactions with proteins and its surroundings with unprecedented resolution, providing a better understanding of these systems and interactions at the nanoscale. Transcriptional profiling, the measure of messenger RNA (mRNA) abundance in a single cell, is a powerful technique that detects "behavior" or "symptoms" at the tissue and cellular level. We have sought to develop an alternative approach, using our expertise in AFM and single molecule nanotechnology, to achieve a cost-effective high throughput method for sensitive detection and profiling of subtle changes in transcript abundance. The technique does not require amplification of the mRNA sample because the AFM provides three-dimensional views of molecules with unprecedented resolution, requires minimal sample preparation, and utilizes a simple tagging chemistry on cDNA molecules. AFM images showed collagen polymers in teeth and of Drebrin-A remodeling of filamentous actin structure and mechanics. AFM was used to image collagen on exposed dentine tubules and confirmed tubule occlusion with a desensitizing prophylaxis paste by Colgate-Palmolive. The AFM also superseded other microscopy tools in resolving F-actin helix remodeling and possible cooperative binding by a neuronal actin binding protein---Drebrin-A, an interaction that can provide scientists with a better understanding of debilitating neurological diseases, such as Alzheimer's and Down Syndrome at the molecular level. These observations provide extraordinary access to the subtle signs and behavior indicating early onset of disease in cells and tissues and to the dynamics of disease development and treatment.

Quantum defect theory for the orbital Feshbach resonance

NASA Astrophysics Data System (ADS)

Cheng, Yanting; Zhang, Ren; Zhang, Peng

2017-01-01

In the ultracold gases of alkali-earth-metal-like atoms, a new type of Feshbach resonance, i.e., the orbital Feshbach resonance (OFR), has been proposed and experimentally observed in ultracold 173Yb atoms [R. Zhang et al., Phys. Rev. Lett. 115, 135301 (2015), 10.1103/PhysRevLett.115.135301]. When the OFR of the 173Yb atoms occurs, the energy gap between the open and closed channels is smaller by two orders of magnitude than the van der Waals energy. As a result, quantitative accurate results for the low-energy two-body problems can be obtained via multichannel quantum defect theory (MQDT), which is based on the exact solution of the Schrödinger equation with the van der Waals potential. In this paper we use MQDT to calculate the two-atom scattering length, effective range, and binding energy of two-body bound states for the systems with OFR. With these results we further study the clock-transition spectrum for the two-body bound states, which can be used to experimentally measure the binding energy. Our results are helpful for the quantitative theoretical and experimental research for the ultracold gases of alkali-earth-metal-like atoms with OFR.

Preparation and DNA-binding properties of substituted triostin antibiotics.

PubMed

Cornish, A; Fox, K R; Waring, M J

1983-02-01

Novel derivatives of the triostin group of antibiotics were prepared by supplementing cultures of the producing organism Streptomyces triostinicus with a variety of aromatic carboxylic acids. Five new antibiotics, each having both the natural quinoxaline chromophores replaced by a substituted ring system, were purified to homogeneity and characterized by high-pressure liquid chromatography and nuclear magnetic resonance. Their antibacterial activities and DNA-binding properties were investigated. Addition of a halogen atom at position 6 of the quinoxaline ring or an amino group at position 3 had little effect on either the biological activity or the DNA-binding characteristics. The bis-3-amino derivative is fluorescent, and its fluorescence is strongly quenched by calf thymus DNA and polydeoxyguanylate-polydeoxycytidylate but not by polydeoxyadenylate-polydeoxythymidylate, suggesting that it binds preferentially to guanosine-cytosine-rich sequences in natural DNA. Binding constants for the bis-6-chloro and bis-3-amino derivatives do not differ greatly from those of unsubstituted triostin A. The analogs having two quinoline chromophores or a chlorine atom in position 7 of the quinoxaline ring display little or no detectable antibacterial activity, in marked contrast to the other congeners. Bis-7-chloro-triostin A binds conspicuously more tightly to polydeoxyadenylate-polydeoxythymidylate than to any other polynucleotide tested.

Condensation and dissociation rates for gas phase metal clusters from molecular dynamics trajectory calculations

DOE PAGES

Yang, Huan; Goudeli, Eirini; Hogan, Christopher J.

2018-04-24

In gas phase synthesis systems, clusters form and grow via condensation, in which a monomer binds to an existing cluster. While a hard sphere equation is frequently used to predict the condensation rate coefficient, this equation neglects the influences of potential interactions and cluster internal energy on the condensation process. Here, we present a collision rate theory-Molecular Dynamics simulation approach to calculate condensation probabilities and condensation rate coefficients; we use this approach to examine atomic condensation onto 6-56 atom Au and Mg clusters. The probability of condensation depends upon the initial relative velocity ( v) between atom and cluster andmore » the initial impact parameter ( b). In all cases there is a well-defined region of b-v space where condensation is highly probable, and outside of which the condensation probability drops to zero. For Au clusters with more than 10 atoms, we find that at gas temperatures in the 300-1200 K range, the condensation rate coefficient exceeds the hard sphere rate coefficient by a factor of 1.5-2.0. Conversely, for Au clusters with 10 or fewer atoms, and for 14 atom and 28 atom Mg clusters, as cluster equilibration temperature increases the condensation rate coefficient drops to values below the hard sphere rate coefficient. Calculations also yield the self-dissociation rate coefficient, which is found to vary considerably with gas temperature. Finally, calculations results reveal that grazing (high b) atom-cluster collisions at elevated velocity (> 1000 m s -1) can result in the colliding atom rebounding (bounce) from the cluster surface or binding while another atom dissociates (replacement). In conclusion, the presented method can be applied in developing rate equations to predict material formation and growth rates in vapor phase systems.« less

Condensation and dissociation rates for gas phase metal clusters from molecular dynamics trajectory calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Huan; Goudeli, Eirini; Hogan, Christopher J.

In gas phase synthesis systems, clusters form and grow via condensation, in which a monomer binds to an existing cluster. While a hard sphere equation is frequently used to predict the condensation rate coefficient, this equation neglects the influences of potential interactions and cluster internal energy on the condensation process. Here, we present a collision rate theory-Molecular Dynamics simulation approach to calculate condensation probabilities and condensation rate coefficients; we use this approach to examine atomic condensation onto 6-56 atom Au and Mg clusters. The probability of condensation depends upon the initial relative velocity ( v) between atom and cluster andmore » the initial impact parameter ( b). In all cases there is a well-defined region of b-v space where condensation is highly probable, and outside of which the condensation probability drops to zero. For Au clusters with more than 10 atoms, we find that at gas temperatures in the 300-1200 K range, the condensation rate coefficient exceeds the hard sphere rate coefficient by a factor of 1.5-2.0. Conversely, for Au clusters with 10 or fewer atoms, and for 14 atom and 28 atom Mg clusters, as cluster equilibration temperature increases the condensation rate coefficient drops to values below the hard sphere rate coefficient. Calculations also yield the self-dissociation rate coefficient, which is found to vary considerably with gas temperature. Finally, calculations results reveal that grazing (high b) atom-cluster collisions at elevated velocity (> 1000 m s -1) can result in the colliding atom rebounding (bounce) from the cluster surface or binding while another atom dissociates (replacement). In conclusion, the presented method can be applied in developing rate equations to predict material formation and growth rates in vapor phase systems.« less

On the Reliability of Pure and Hybrid DFT Methods for the Evaluation of Halogen, Chalcogen, and Pnicogen Bonds Involving Anionic and Neutral Electron Donors.

PubMed

Bauzá, Antonio; Alkorta, Ibon; Frontera, Antonio; Elguero, José

2013-11-12

In this article, we report a comprehensive theoretical study of halogen, chalcogen, and pnicogen bonding interactions using a large set of pure and hybrid functionals and some ab initio methods. We have observed that the pure and some hybrid functionals largely overestimate the interaction energies when the donor atom is anionic (Cl(-) or Br(-)), especially in the halogen bonding complexes. To evaluate the reliability of the different DFT (BP86, BP86-D3, BLYP, BLYP-D3, B3LYP, B97-D, B97-D3, PBE0, HSE06, APFD, and M06-2X) and ab initio (MP2, RI-MP2, and HF) methods, we have compared the binding energies and equilibrium distances to those obtained using the CCSD(T)/aug-cc-pVTZ level of theory, as reference. The addition of the latest available correction for dispersion (D3) to pure functionals is not recommended for the calculation of halogen, chalcogen, and pnicogen complexes with anions, since it further contributes to the overestimation of the binding energies. In addition, in chalcogen bonding interactions, we have studied how the hybridization of the chalcogen atom influences the interaction energies.

Element specificity of ortho-positronium annihilation for alkali-metal loaded SiO2 glasses.

PubMed

Sato, K; Hatta, T

2015-03-07

Momentum distributions associated with ortho-positronium (o-Ps) pick-off annihilation photon are often influenced by light elements, as, e.g., carbon, oxygen, and fluorine. This phenomenon, so-called element specificity of o-Ps pick-off annihilation, has been utilized for studying the elemental environment around the open spaces. To gain an insight into the element specificity of o-Ps pick-off annihilation, the chemical shift of oxygen 1s binding energy and the momentum distributions associated with o-Ps pick-off annihilation were systematically investigated for alkali-metal loaded SiO2 glasses by means of X-ray photoelectron spectroscopy and positron-age-momentum correlation spectroscopy, respectively. Alkali metals introduced into the open spaces surrounded by oxygen atoms cause charge transfer from alkali metals to oxygen atoms, leading to the lower chemical shift for the oxygen 1s binding energy. The momentum distribution of o-Ps localized into the open spaces is found to be closely correlated with the oxygen 1s chemical shift. This correlation with the deepest 1s energy level evidences that the element specificity of o-Ps originates from pick-off annihilation with orbital electrons, i.e., dominantly with oxygen 2p valence electrons and s electrons with lower probability.

Converging ligand-binding free energies obtained with free-energy perturbations at the quantum mechanical level.

PubMed

Olsson, Martin A; Söderhjelm, Pär; Ryde, Ulf

2016-06-30

In this article, the convergence of quantum mechanical (QM) free-energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158-224 atoms). We use single-step exponential averaging (ssEA) and the non-Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi-empirical PM6-DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free-energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

Converging ligand‐binding free energies obtained with free‐energy perturbations at the quantum mechanical level

PubMed Central

Olsson, Martin A.; Söderhjelm, Pär

2016-01-01

In this article, the convergence of quantum mechanical (QM) free‐energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa‐acid deep‐cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158–224 atoms). We use single‐step exponential averaging (ssEA) and the non‐Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi‐empirical PM6‐DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free‐energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID:27117350

Glucose monitoring using a polymer brush modified polypropylene hollow fiber-based hydraulic flow sensor.

PubMed

Fortin, Nicolas; Klok, Harm-Anton

2015-03-04

Tight regulation of blood glucose levels of diabetic patients requires durable and robust continuous glucose sensing schemes. This manuscript reports the fabrication of ultrathin, phenylboronic acid (PBA) functionalized polymer brushes that swell upon glucose binding and which were integrated as the sensing interface in a new polypropylene hollow fiber (PPHF)-based hydraulic flow glucose sensor prototype. The polymer brushes were prepared via surface-initiated atom transfer radical polymerization of sodium methacrylate followed by postpolymerization modification with 3-aminophenyl boronic acid. In a first series of experiments, the glucose-response of PBA-functionalized poly(methacrylic acid) (PMAA) brushes grafted from planar silicon surfaces was investigated by quartz crystal microbalance with dissipation (QCM-D) and atomic force microscopy (AFM) experiments. The QCM-D experiments revealed a more or less linear change of the frequency shift for glucose concentrations up to ∼10 mM and demonstrated that glucose binding was completely reversible for up to seven switching cycles. The AFM experiments indicated that glucose binding was accompanied by an increase in the film thickness of the PBA functionalized PMAA brushes. The PBA functionalized PMAA brushes were subsequently grafted from the surface of PPHF membranes. The hydraulic permeability of these porous fibers depends on the thickness and swelling of the PMAA brush coating. PBA functionalized brush-coated PPHFs showed a decrease in flux upon exposure to glucose, which is consistent with swelling of the brush coating. Because they avoid the use of enzymes and do not rely on an electrochemical transduction scheme, these PPHF-based hydraulic flow sensors could represent an interesting alternative class of continuous glucose sensors.

Dual nature of acceptors in GaN and ZnO: The curious case of the shallow MgGa deep state

NASA Astrophysics Data System (ADS)

Lany, Stephan; Zunger, Alex

2010-04-01

Employing a Koopmans corrected density functional method, we find that the metal-site acceptors Mg, Be, and Zn in GaN and Li in ZnO bind holes in deep levels that are largely localized at single anion ligand atoms. In addition to this deep ground state (DGS), we observe an effective-masslike delocalized state that can exist as a short lived shallow transient state (STS). The Mg dopant in GaN represents the unique case where the ionization energy of the localized deep level exceeds only slightly that of the shallow effective-mass acceptor, which explains why Mg works so exceptionally well as an acceptor dopant.

Two different carbon-hydrogen complexes in silicon with closely spaced energy levels

NASA Astrophysics Data System (ADS)

Stübner, R.; Kolkovsky, Vl.; Weber, J.

2015-08-01

An acceptor and a single donor state of carbon-hydrogen defects (CHA and CHB) are observed by Laplace deep level transient spectroscopy at 90 K. CHA appears directly after hydrogenation by wet chemical etching or hydrogen plasma treatment, whereas CHB can be observed only after a successive annealing under reverse bias at about 320 K. The activation enthalpies of these states are 0.16 eV for CHA and 0.14 eV for CHB. Our results reconcile previous controversial experimental results. We attribute CHA to the configuration where substitutional carbon binds a hydrogen atom on a bond centered position between carbon and the neighboring silicon and CHB to another carbon-hydrogen defect.

Generation of the first structure-based pharmacophore model containing a selective "zinc binding group" feature to identify potential glyoxalase-1 inhibitors.

PubMed

Al-Balas, Qosay; Hassan, Mohammad; Al-Oudat, Buthina; Alzoubi, Hassan; Mhaidat, Nizar; Almaaytah, Ammar

2012-11-22

Within this study, a unique 3D structure-based pharmacophore model of the enzyme glyoxalase-1 (Glo-1) has been revealed. Glo-1 is considered a zinc metalloenzyme in which the inhibitor binding with zinc atom at the active site is crucial. To our knowledge, this is the first pharmacophore model that has a selective feature for a "zinc binding group" which has been customized within the structure-based pharmacophore model of Glo-1 to extract ligands that possess functional groups able to bind zinc atom solely from database screening. In addition, an extensive 2D similarity search using three diverse similarity techniques (Tanimoto, Dice, Cosine) has been performed over the commercially available "Zinc Clean Drug-Like Database" that contains around 10 million compounds to help find suitable inhibitors for this enzyme based on known inhibitors from the literature. The resultant hits were mapped over the structure based pharmacophore and the successful hits were further docked using three docking programs with different pose fitting and scoring techniques (GOLD, LibDock, CDOCKER). Nine candidates were suggested to be novel Glo-1 inhibitors containing the "zinc binding group" with the highest consensus scoring from docking.

Equilibrium structure and atomic vibrations of Nin clusters

NASA Astrophysics Data System (ADS)

Borisova, Svetlana D.; Rusina, Galina G.

2017-12-01

The equilibrium bond lengths and binding energy, second differences in energy and vibrational frequencies of free clusters Nin (2 ≤ n ≤ 20) were calculated with the use of the interaction potential obtained in the tight-binding approximation (TBA). The results show that the minimum vibration frequency plays a significant role in the evaluation of the dynamic stability of the clusters. A nonmonotonic dependence of the minimum vibration frequency of clusters on their size and the extreme values for the number of atoms in a cluster n = 4, 6, 13, and 19 are demonstrated. This result agrees with the theoretical and experimental data on stable structures of small metallic clusters.

Hybrid k .p tight-binding model for intersubband optics in atomically thin InSe films

NASA Astrophysics Data System (ADS)

Magorrian, S. J.; Ceferino, A.; Zólyomi, V.; Fal'ko, V. I.

2018-04-01

We propose atomic films of n -doped γ -InSe as a platform for intersubband optics in the infrared and far-infrared range, coupled to out-of-plane polarized light. Depending on the film thickness (number of layers) and the amount of n -doping of the InSe film, these transitions span from ˜0.7 eV for bilayer to ˜0.05 eV for 15-layer InSe. We use a hybrid k .p theory and tight-binding model, fully parametrized using density-functional theory, to predict their oscillator strengths and thermal linewidths at room temperature.

Optical binding with cold atoms

NASA Astrophysics Data System (ADS)

Máximo, C. E.; Bachelard, R.; Kaiser, R.

2018-04-01

Optical binding is a form of light-mediated forces between elements of matter which emerge in response to the collective scattering of light. Such a phenomenon has been studied mainly in the context of the equilibrium stability of dielectric sphere arrays which move amid dissipative media. In this article, we demonstrate that optically bounded states of a pair of cold atoms can exist, in the absence of nonradiative damping. We study the scaling laws for the unstable-stable phase transition at negative detuning and the unstable-metastable one for positive detuning. In addition, we show that angular momentum can lead to dynamical stabilization with infinite-range scaling.

On the nature of the {SO2-4}/{Ag(111) } and {SO2-4}/{Au(111) } surface bonding

NASA Astrophysics Data System (ADS)

Patrito, E. M.; Olivera, P. Paredes; Sellers, Harrell

1997-05-01

The nature of sulfate-Ag(111) and sulfate-Au(111) surface bonding has been investigated at the SCF + MP2 level of theory. Convergence of binding energy with cluster size is investigated and, unlike neutral adsorbates, large clusters are required in order to obtain reliable binding energies. In the most stable adsorption mode, sulfate binds to the surface via three oxygen atoms (C 3v symmetry) with a binding energy of 159.3 kcal/mol on Ag(111) and 143.9 kcal/mol on Au(111). The geometry of adsorbed sulfate was optimized at the SCF level. While the bond length between sulfur and the oxygens coordinated to the surface increases, the sulfur-uncoordinated oxygen bond length decreases. This weakening and strengthening of the bonds, respectively, is consistent with bond order conservation in adsorbates on metal surfaces. Although a charge transfer of 0.4 electrons towards the metal is observed, the adsorbate remains very much sulfate-like. The molecular orbital analysis indicates that there is also some charge back-donation towards unoccupied orbitals of sulfate. This results in an increased electron density around sulfur as revealed in the electron density difference maps. Analysis of the Laplacian of the charge density of free sulfate provides a suitable framework to understand the nature of the different charge transfer processes and allows us to establish some similarities with the CO- and SO 2-metal bondings.

The electronic structure of Bi 2.0Sr 1.8La 0.3Ca 0.8Cu 2.1O 8+δ superconductors studied using ultraviolet and X-ray photoelectron spectroscopy

NASA Astrophysics Data System (ADS)

Lindberg, P. A. P.; Shen, Z.-X.; Dessau, D. S.; Wells, B. O.; Borg, A.; Ellis, W.; Mitzi, D. B.; Lindau, I.; Spicer, W. E.; Kapitulnik, A.

1989-07-01

Photoemission measurements on single crystals of La-doped 2212 (Bi 2.0Sr 1.8La 0.3Ca 0.8Cu 2.1O 8+δ) superconductors were carried out utilizing both synchrotron and Al K α (1486.6 eV) radiation. A quantitative analysis of the photoemission data in comparison with similar data for the undoped 2212 material indicates that the La atoms preferentially occupy the Sr sites in the SrO layer next to the BiO plane. Evidence of alternation of the electronic environment of the Bi atoms is found in the Bi 5d core level spectra which show a shoulder at ≈ 1.2 eV higher binding energy, presumably due to the partial substitution of trivalent La ions (La 3+) for divalent Sr ions (Sr 2+). As for the undoped 2212 material, the photoemission spectra reveal a clear Fermi level cut-off at room temperature, single component O ls core level emission, and a Cu 2p satellite to main line intensity ratio of 0.4.

Importance of length and sequence order on magnesium binding to surface-bound oligonucleotides studied by second harmonic generation and atomic force microscopy.

PubMed

Holland, Joseph G; Geiger, Franz M

2012-06-07

The binding of magnesium ions to surface-bound single-stranded oligonucleotides was studied under aqueous conditions using second harmonic generation (SHG) and atomic force microscopy (AFM). The effect of strand length on the number of Mg(II) ions bound and their free binding energy was examined for 5-, 10-, 15-, and 20-mers of adenine and guanine at pH 7, 298 K, and 10 mM NaCl. The binding free energies for adenine and guanine sequences were calculated to be -32.1(4) and -35.6(2) kJ/mol, respectively, and invariant with strand length. Furthermore, the ion density for adenine oligonucleotides did not change as strand length increased, with an average value of 2(1) ions/strand. In sharp contrast, guanine oligonucleotides displayed a linear relationship between strand length and ion density, suggesting that cooperativity is important. This data gives predictive capabilities for mixed strands of various lengths, which we exploit for 20-mers of adenines and guanines. In addition, the role sequence order plays in strands of hetero-oligonucleotides was examined for 5'-A(10)G(10)-3', 5'-(AG)(10)-3', and 5'-G(10)A(10)-3' (here the -3' end is chemically modified to bind to the surface). Although the free energy of binding is the same for these three strands (averaged to be -33.3(4) kJ/mol), the total ion density increases when several guanine residues are close to the 3' end (and thus close to the solid support substrate). To further understand these results, we analyzed the height profiles of the functionalized surfaces with tapping-mode atomic force microscopy (AFM). When comparing the average surface height profiles of the oligonucleotide surfaces pre- and post- Mg(II) binding, a positive correlation was found between ion density and the subsequent height decrease following Mg(II) binding, which we attribute to reductions in Coulomb repulsion and strand collapse once a critical number of Mg(II) ions are bound to the strand.

Antimatter Transport Processes

NASA Astrophysics Data System (ADS)

van der Werf, D. P.; Andresen G. B.; Ashkezari, M. D.; Baquero-Ruiz, M.; Bertsche W.; Bowe, P. D.; Bray, C. C.; Butler, E.; Cesar, C. L.; Chapman, S.; Charlton, M.; Fajans, J.; Friesen, T.; Fujiwara, M. C.; Gill, D. R.; Hangst, J. S.; Hardy, W. N.; Hayano, R. S.; Hayden, M. E.; Humphries, A. J.; Hydomako, R.; Jonsell, S.; Kurchaninov, L.; Lambo, R.; Madsen, N.; Menary, S.; Nolan, P.; Olchanski, K.; Olin, A.; Povilus, A.; Pusa, P.; Robicheaux, F.; Sarid, E.; Silveira, D. M.; So, C.; Storey, J. W.; Thompson, R. I.; Wilding, D.; Wurtele, J. S.; Yamazaki, Y.; Alpha Collaboration

2010-07-01

The comparison of the 1S-2S energy levels of hydrogen and antihydrogen will yield a stringent test of CPT conservation. Necessarily, the antihydrogen atoms need to be trapped to perform high precision spectroscopy measurements. Therefore, an approximately 1 T deep neutral trap, about 0.7 K for ground state (anti)hydrogen atoms, has been superimposed on a Penning-Malmberg trap in which the antiatoms are formed. The antihydrogen atoms, which are required to have a low enough kinetic energy to be trapped, are produced following a number of steps. A bunch of antiprotons from the CERN Antiproton Decelerator are caught in a Penning-Malmberg trap and subsequently sympathetically cooled down and then compressed using rotating wall electric fields. A positron plasma, formed in a separate accumulator, is transported to the main system and also compressed. Antihydrogen atoms are then formed by mixing the antiprotons and positrons. The velocity of the antiatoms, and their binding energies, will strongly depend on the initial conditions of the constituent particles, for example their temperatures and densities, and on the details of the mixing process. In this talk the complete lifecycle of antihydrogen atoms will be presented, starting with the production of the constituent particles and the description of the manipulations necessary to prepare positrons and antiprotons appropriately for antihydrogen formation. The latter will also be described, as will the possible fates of the antiatoms.

Hydrogen molecules and chains in a superstrong magnetic field

NASA Technical Reports Server (NTRS)

Lai, Dong; Salpeter, Edwin E.; Shapiro, Stuart L.

1992-01-01

The electronic structures of hydrogen polymolecules H(n) (n = 2,3,4,...) is studied in a superstrong magnetic field (B greater than about 10 exp 12 G) typically found on the surface of a neutron star. Simple analytical scaling relations for several limiting cases (e.g., large n, high B field) are derived. The binding energies of H(n) molecules are numerically calculated for various magnetic-field strengths. For a given magnetic-field strength, the binding energy per atom in the H(n) molecules is found to approach a constant value as n increases. For typical field strengths of interest, energy saturation is essentially achieved once n exceeds 3 to 4. Also considered is the structure of negative H ions in a high magnetic field. For B about 10 exp 12 G, the dissociation energy of an atom in a hydrogen chain and the ionization potential of H(-) are smaller than the ionization potential of neutral atomic hydrogen.

Annealing induced atomic rearrangements on (Ga,In) (N,As) probed by hard X-ray photoelectron spectroscopy and X-ray absorption fine structure.

PubMed

Ishikawa, Fumitaro; Higashi, Kotaro; Fuyuno, Satoshi; Morifuji, Masato; Kondow, Masahiko; Trampert, Achim

2018-04-13

We study the effects of annealing on (Ga 0.64 ,In 0.36 ) (N 0.045 ,As 0.955 ) using hard X-ray photoelectron spectroscopy and X-ray absorption fine structure measurements. We observed surface oxidation and termination of the N-As bond defects caused by the annealing process. Specifically, we observed a characteristic chemical shift towards lower binding energies in the photoelectron spectra related to In. This phenomenon appears to be caused by the atomic arrangement, which produces increased In-N bond configurations within the matrix, as indicated by the X-ray absorption fine structure measurements. The reduction in the binding energies of group-III In, which occurs concomitantly with the atomic rearrangements of the matrix, causes the differences in the electronic properties of the system before and after annealing.

Evidence for calcium soaps in human hair shaft revealed by sub-micrometer X-ray fluorescence

NASA Astrophysics Data System (ADS)

Briki, F.; Mérigoux, C.; Sarrot-Reynauld, F.; Salomé, M.; Fayard, B.; Susini, J.; Doucet, J.

2003-03-01

New information about calcium status in human scalp hair shaft, deduced from X-ray microfluorescence imaging, including its distribution over the hair section, the existence of one or several binding-types and its variation between people, is presented. The existence of two different calcium types is inferred. The first one corresponds to atoms (or ions) easily removable by hydrochloric acid, located in the cortex (granules), in the cuticle zone and also in the core of the medulla, which are identified as calcium soaps cy comparison with X-ray diffraction and IR spectromicroscopy data. The second type consists of non-easily removable calcium atoms (or ions) that are located in the medulla wall, probably also the cuticle, and rather uniformly in the cortex; these calcium atoms may be involved in Ca^{2+}-binding proteins, their concentration is fairly constant from one subject to another.

Morphology variation, composition alteration and microstructure changes in ion-irradiated 1060 aluminum alloy

NASA Astrophysics Data System (ADS)

Wan, Hao; Si, Naichao; Wang, Quan; Zhao, Zhenjiang

2018-02-01

Morphology variation, composition alteration and microstructure changes in 1060 aluminum irradiated with 50 keV helium ions were characterized by field emission scanning electron microscopy (FESEM) equipped with x-ray elemental scanning, 3D measuring laser microscope and transmission electron microscope (TEM). The results show that, helium ions irradiation induced surface damage and Si-rich aggregates in the surfaces of irradiated samples. Increasing the dose of irradiation, more damages and Si-rich aggregates would be produced. Besides, defects such as dislocations, dislocation loops and dislocation walls were the primary defects in the ion implanted layer. The forming of surface damages were related with preferentially sputtering of Al component. While irradiation-enhanced diffusion and irradiation-induced segregation resulted in the aggregation of impurity atoms. And the aggregation ability of impurity atoms were discussed based on the atomic radius, displacement energy, lattice binding energy and surface binding energy.

Formation of ultracold molecules induced by a high-power single frequency fiber laser

NASA Astrophysics Data System (ADS)

Fernandes Passagem, Henry; Colin-Rodriguez, Ricardo; Ventura da Silva, Paulo; Bouloufa-Maafa, Nadia; Dulieu, Olivier; Marcassa, Luis

2017-04-01

Photoassociation of a pair of ultracold atoms is a quite simple and rapid approach for cold molecule formation. The main limitation of PA is that the latter step is incoherent, so that the population of the created molecules is spread over many vibrational levels with weak or moderate binding energies. If the excited electronic molecular state exhibits a peculiar feature at short internuclear distance like a potential barrier or an avoided crossing, the population of deeply-bound ground state levels may be significantly enhanced. In this work, the influence of a high-power single frequency fiber laser on the formation of ultracold 85Rb2 molecules is investigated as a function of its frequency (in the 1062-1070 nm range) in a magneto optical trap. We found evidence for the formation of ground state 85Rb2 molecules in low vibrational levels (v <= 20) with a maximal rate of 104 s-1, induced by short-range photoassociation by the fiber laser followed by spontaneous emission. When this laser is used to set up a dipole trap, we measure an atomic loss rate at a wavelength far from the PA resonances only 4 times smaller than the one observed at a PA resonance wavelength. This work may have important consequences for atom trapping using lasers around 1060 nm. This work is supported by Grants 2013/02816-8 and 2014/24479-6, Sao Paulo Research Foundation (FAPESP).

Near-atomic model of microtubule-tau interactions.

PubMed

Kellogg, Elizabeth H; Hejab, Nisreen M A; Poepsel, Simon; Downing, Kenneth H; DiMaio, Frank; Nogales, Eva

2018-06-15

Tau is a developmentally regulated axonal protein that stabilizes and bundles microtubules (MTs). Its hyperphosphorylation is thought to cause detachment from MTs and subsequent aggregation into fibrils implicated in Alzheimer's disease. It is unclear which tau residues are crucial for tau-MT interactions, where tau binds on MTs, and how it stabilizes them. We used cryo-electron microscopy to visualize different tau constructs on MTs and computational approaches to generate atomic models of tau-tubulin interactions. The conserved tubulin-binding repeats within tau adopt similar extended structures along the crest of the protofilament, stabilizing the interface between tubulin dimers. Our structures explain the effect of phosphorylation on MT affinity and lead to a model of tau repeats binding in tandem along protofilaments, tethering together tubulin dimers and stabilizing polymerization interfaces. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

CO adsorption on (111) and (100) surfaces of the Pt sub 3 Ti alloy. Evidence for parallel binding and strong activation of CO

NASA Technical Reports Server (NTRS)

Mehandru, S. P.; Anderson, A. B.; Ross, P. N.

1985-01-01

The CO adsorption on a 40 atom cluster model of the (111) surface and a 36 atom cluster model of the (100) surface of the Pt3Ti alloy was studied. Parallel binding to high coordinate sites associated with Ti and low CO bond scission barriers are predicted for both surfaces. The binding of CO to Pt sites occurs in an upright orientation. These orientations are a consequence of the nature of the CO pi donation interactions with the surface. On the Ti sites the orbitals donate to the nearly empty Ti 3d band and the antibonding counterpart orbitals are empty. On the Pt sites, however, they are in the filled Pt 5d region of the alloy band, which causes CO to bond in a vertical orientation by 5 delta donation from the carbon end.

Molecular modeling and multispectroscopic studies of the interaction of mesalamine with bovine serum albumin

NASA Astrophysics Data System (ADS)

Shahabadi, Nahid; Fili, Soraya Moradi

2014-01-01

The interaction of mesalamine (5-aminosalicylic acid (5-ASA)) with bovine serum albumin (BSA) was investigated by fluorescence quenching, absorption spectroscopy, circular dichroism (CD) techniques, and molecular docking. Thermodynamic parameters (ΔH < 0 and ΔS 0) indicated that the hydrogen bond and electrostatic forces played the major role in the binding of 5-ASA to BSA. The results of CD and UV-vis spectroscopy showed that the binding of this drug to BSA induces some conformational changes in BSA. Displacement experiments predicted that the binding of 5-ASA to BSA is located within domain III, Sudlows site 2, that these observations were substantiated by molecular docking studies. In addition, the docking result shows that the 5-ASA in its anionic form mainly interacts with Gln-416 residue through one hydrogen bond between H atom of 5-ASA anion and the adjacent O atom of the hydroxyl group of Gln-416.

Automated docking of ligands to an artificial active site: augmenting crystallographic analysis with computer modeling

NASA Astrophysics Data System (ADS)

Rosenfeld, Robin J.; Goodsell, David S.; Musah, Rabi A.; Morris, Garrett M.; Goodin, David B.; Olson, Arthur J.

2003-08-01

The W191G cavity of cytochrome c peroxidase is useful as a model system for introducing small molecule oxidation in an artificially created cavity. A set of small, cyclic, organic cations was previously shown to bind in the buried, solvent-filled pocket created by the W191G mutation. We docked these ligands and a set of non-binders in the W191G cavity using AutoDock 3.0. For the ligands, we compared docking predictions with experimentally determined binding energies and X-ray crystal structure complexes. For the ligands, predicted binding energies differed from measured values by ± 0.8 kcal/mol. For most ligands, the docking simulation clearly predicted a single binding mode that matched the crystallographic binding mode within 1.0 Å RMSD. For 2 ligands, where the docking procedure yielded an ambiguous result, solutions matching the crystallographic result could be obtained by including an additional crystallographically observed water molecule in the protein model. For the remaining 2 ligands, docking indicated multiple binding modes, consistent with the original electron density, suggesting disordered binding of these ligands. Visual inspection of the atomic affinity grid maps used in docking calculations revealed two patches of high affinity for hydrogen bond donating groups. Multiple solutions are predicted as these two sites compete for polar hydrogens in the ligand during the docking simulation. Ligands could be distinguished, to some extent, from non-binders using a combination of two trends: predicted binding energy and level of clustering. In summary, AutoDock 3.0 appears to be useful in predicting key structural and energetic features of ligand binding in the W191G cavity.

A DFT study of the stability of SIAs and small SIA clusters in the vicinity of solute atoms in Fe

NASA Astrophysics Data System (ADS)

Becquart, C. S.; Ngayam Happy, R.; Olsson, P.; Domain, C.

2018-03-01

The energetics, defect volume and magnetic properties of single SIAs and small SIA clusters up to size 6 have been calculated by DFT for different configurations like the parallel 〈110〉 dumbbell, the non parallel 〈110〉 dumbbell and the C15 structure. The most stable configurations of each type have been further analyzed to determine the influence on their stability of various solute atoms (Ti, V, Cr, Mn, Co, Ni, Cu, Mo, W, Pd, Al, Si, P), relevant for steels used under irradiation. The results show that the presence of solute atoms does not change the relative stability order among SIA clusters. The small SIA clusters investigated can bind to both undersized and oversized solutes. Several descriptors have been considered to derive interesting trends from results. It appears that the local atomic volume available for the solute is the main physical quantity governing the binding energy evolution, whatever the solute type (undersized or oversized) and the cluster configuration (size and type).

Structural mechanism underlying capsaicin binding and activation of TRPV1 ion channel

PubMed Central

Cheng, Wei; Yang, Wei; Yu, Peilin; Song, Zhenzhen; Yarov-Yarovoy, Vladimir; Zheng, Jie

2015-01-01

Capsaicin bestows spiciness by activating TRPV1 channel with exquisite potency and selectivity. Capsaicin-bound channel structure was previously resolved by cryo-EM at 4.2-to-4.5 Å resolution, however important details required for mechanistic understandings are unavailable: capsaicin was registered as a small electron density, reflecting neither its chemical structure nor specific ligand-channel interactions. We obtained the missing atomic-level details by iterative computation, which were confirmed by systematic site-specific functional tests. We observed that the bound capsaicin takes “tail-up, head-down” configurations. The vanillyl and amide groups form specific interactions to anchor its bound position, while the aliphatic tail may sample a range of conformations, making it invisible in cryo-EM images. Capsaicin stabilizes the open state by “pull-and-contact” interactions between the vanillyl group and the S4-S5 linker. Our study provided a structural mechanism for the agonistic function of capsaicin and its analogs, and demonstrated an effective approach to obtain atomic level information from cryo-EM structures. PMID:26053297

Beneficial Effects of the Amino Acid Glycine.

PubMed

Pérez-Torres, Israel; Zuniga-Munoz, Alejandra María; Guarner-Lans, Veronica

2017-01-01

Glycine is the smallest non-essential, neutral and metabolically inert amino acid, with a carbon atom bound to two hydrogen atoms, and to an amino and a carboxyl group. This amino acid is an essential substrate for the synthesis of several biologically important biomolecules and compounds. It participates in the synthesis of proteins, of the tripeptide glutathione and in detoxification reactions. It has a broad spectrum of anti-inflammatory, cytoprotective and immunomodulatory properties. To exert its actions, glycine binds to different receptors. The GlyR anion channel is the most studied receptor for glycine. However, there are GlyR-independent mechanisms for glycine cytoprotection and other possible binding molecules of glycine are the NMDA receptor and receptors GlyT1 and GlyT2. Although, in humans, the normal serum level of glycine is approximately 300 μM, increasing glycine intake can lead to blood levels of more than 900 μM that increase its benefic actions without having harmful side effects. The herbal pesticide glyphosate might disrupt glycine homeostasis. Many in vitro studies involving different cell types have demonstrated beneficial effects of the addition of glycine. Glycine also improved conditions of isolated perfused or stored organs. In vivo studies in experimental animals have also tested glycine as a protector molecule and some studies on the beneficial effects of glycine after its clinical application have been done. Although at high-doses, glycine may cause toxic effects, further studies are needed to investigate the safe range of usage of this aminoacid and to test the diverse routes of administration.

Study of p-diaminobenzene Adsorption on Au(111) by Scanning Tunneling Microscopy

NASA Astrophysics Data System (ADS)

Zhou, Hui; Hu, Zonghai; Eom, Daejin; Rim, Kwang; Liu, Li; Flynn, George; Venkataraman, Latha; Morgante, Alberto; Heinz, Tony

2008-03-01

From the well-defined conductivity obtained for various individual diamino-substituted molecules spanning two gold contacts, as well as from theoretical analysis [1], researchers have suggested that amines adsorb preferentially to coordinatively unsaturated surface Au atoms through the N lone pair. To understand the nature of the amine binding, we have applied ultrahigh vacuum scanning tunneling microscope (STM) to investigate the adsorption of p-diaminobenzene molecules on the reconstructed Au(111) surface. The STM topography images (taken at 4 K) show that the molecules adsorb preferentially to step edges, corresponding to sites of reduced Au atom coordination. The adsorbed molecules are found to display a distinctive orientation along the step edges. The two-lobe topographic structure of each molecule seen by STM is compatible with the previously calculated charge density of the HOMO level. [1] L. Venkataraman at el., Nano Lett. 7, 502 (2007).

An ab initio study on BeX 3- superhalogen anions (X = F, Cl, Br)

NASA Astrophysics Data System (ADS)

Anusiewicz, Iwona; Skurski, Piotr

2002-06-01

The vertical electron detachment energies (VDE) of 10 BeX 3- (X = F, Cl, Br) anions were calculated at the outer valence Green function (OVGF) level with the 6-311++G(3df) basis sets. The largest vertical electron binding energy was found for BeF 3- system (7.63 eV). All negatively charged species possess the vertical electron detachment energies that are larger than 5.5 eV and thus may be termed superhalogen anions. The strong dependence of the VDE of the BeX 3- species on the ligand-central atom (Be-X) distance and on the partial atomic charge localized on Be was observed and discussed, as well as the other factors that may influence the electronic stability of such anions. In addition, the usefulness of the various theoretical treatments for estimating the VDEs of superhalogen anions was tested and analyzed.

Condensation and dissociation rates for gas phase metal clusters from molecular dynamics trajectory calculations.

PubMed

Yang, Huan; Goudeli, Eirini; Hogan, Christopher J

2018-04-28

In gas phase synthesis systems, clusters form and grow via condensation, in which a monomer binds to an existing cluster. While a hard-sphere equation is frequently used to predict the condensation rate coefficient, this equation neglects the influences of potential interactions and cluster internal energy on the condensation process. Here, we present a collision rate theory-molecular dynamics simulation approach to calculate condensation probabilities and condensation rate coefficients. We use this approach to examine atomic condensation onto 6-56-atom Au and Mg clusters. The probability of condensation depends upon the initial relative velocity (v) between atom and cluster and the initial impact parameter (b). In all cases, there is a well-defined region of b-v space where condensation is highly probable, and outside of which the condensation probability drops to zero. For Au clusters with more than 10 atoms, we find that at gas temperatures in the 300-1200 K range, the condensation rate coefficient exceeds the hard-sphere rate coefficient by a factor of 1.5-2.0. Conversely, for Au clusters with 10 or fewer atoms and for 14- and 28-atom Mg clusters, as cluster equilibration temperature increases, the condensation rate coefficient drops to values below the hard-sphere rate coefficient. Calculations also yield the self-dissociation rate coefficient, which is found to vary considerably with gas temperature. Finally, calculations results reveal that grazing (high b) atom-cluster collisions at elevated velocity (>1000 m s -1 ) can result in the colliding atom rebounding (bounce) from the cluster surface or binding while another atom dissociates (replacement). The presented method can be applied in developing rate equations to predict material formation and growth rates in vapor phase systems.

Condensation and dissociation rates for gas phase metal clusters from molecular dynamics trajectory calculations

NASA Astrophysics Data System (ADS)

Yang, Huan; Goudeli, Eirini; Hogan, Christopher J.

2018-04-01

In gas phase synthesis systems, clusters form and grow via condensation, in which a monomer binds to an existing cluster. While a hard-sphere equation is frequently used to predict the condensation rate coefficient, this equation neglects the influences of potential interactions and cluster internal energy on the condensation process. Here, we present a collision rate theory-molecular dynamics simulation approach to calculate condensation probabilities and condensation rate coefficients. We use this approach to examine atomic condensation onto 6-56-atom Au and Mg clusters. The probability of condensation depends upon the initial relative velocity (v) between atom and cluster and the initial impact parameter (b). In all cases, there is a well-defined region of b-v space where condensation is highly probable, and outside of which the condensation probability drops to zero. For Au clusters with more than 10 atoms, we find that at gas temperatures in the 300-1200 K range, the condensation rate coefficient exceeds the hard-sphere rate coefficient by a factor of 1.5-2.0. Conversely, for Au clusters with 10 or fewer atoms and for 14- and 28-atom Mg clusters, as cluster equilibration temperature increases, the condensation rate coefficient drops to values below the hard-sphere rate coefficient. Calculations also yield the self-dissociation rate coefficient, which is found to vary considerably with gas temperature. Finally, calculations results reveal that grazing (high b) atom-cluster collisions at elevated velocity (>1000 m s-1) can result in the colliding atom rebounding (bounce) from the cluster surface or binding while another atom dissociates (replacement). The presented method can be applied in developing rate equations to predict material formation and growth rates in vapor phase systems.

SU-C-204-03: DFT Calculations of the Stability of DOTA-Based-Radiopharmaceuticals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khabibullin, A.R.; Woods, L.M.; Karolak, A.

2016-06-15

Purpose: Application of the density function theory (DFT) to investigate the structural stability of complexes applied in cancer therapy consisting of the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelated to Ac225, Fr221, At217, Bi213, and Gd68 radio-nuclei. Methods: The possibility to deliver a toxic payload directly to tumor cells is a highly desirable aim in targeted alpha particle therapy. The estimation of bond stability between radioactive atoms and the DOTA chelating agent is the key element in understanding the foundations of this delivery process. Thus, we adapted the Vienna Ab-initio Simulation Package (VASP) with the projector-augmented wave method and a plane-wave basis setmore » in order to study the stability and electronic properties of DOTA ligand chelated to radioactive isotopes. In order to count for the relativistic effect of radioactive isotopes we included Spin-Orbit Coupling (SOC) in the DFT calculations. Five DOTA complex structures were represented as unit cells, each containing 58 atoms. The energy optimization was performed for all structures prior to calculations of electronic properties. Binding energies, electron localization functions as well as bond lengths between atoms were estimated. Results: Calculated binding energies for DOTA-radioactive atom systems were −17.792, −5.784, −8.872, −13.305, −18.467 eV for Ac, Fr, At, Bi and Gd complexes respectively. The displacements of isotopes in DOTA cages were estimated from the variations in bond lengths, which were within 2.32–3.75 angstroms. The detailed representation of chemical bonding in all complexes was obtained with the Electron Localization Function (ELF). Conclusion: DOTA-Gd, DOTA-Ac and DOTA-Bi were the most stable structures in the group. Inclusion of SOC had a significant role in the improvement of DFT calculation accuracy for heavy radioactive atoms. Our approach is found to be proper for the investigation of structures with DOTA-based-radiopharmaceuticals and will enhance our understanding of processes occurring at subatomic levels.« less

A binding energy study of the Atomic Mass Evaluation 2012 and an updated beta-decay study of neutron-rich 74Cu

NASA Astrophysics Data System (ADS)

Tracy, James L., Jr.

A study of ground state binding energy values listed in the Atomic Mass Evaluation 2012 (AME2012) using an interpretive approach, as opposed to the exploratory methods of previous models, is presented. This model is based on a postulate requiring all protons to pair with available neutrons to form bound alpha clusters as the ground state for an N = Z core upon which excess neutrons are added. For each core, the trend of the binding energy as a function of excess neutrons in the isotopic chain can be fit with a three-term quadratic function. The quadratic parameter reveals a smooth decaying exponential function. By re-envisioning the determination of mass excess, the constant-term fit parameters, representing N = Z nuclei, reveal a near-symmetry around Z = 50. The linear fit parameters exhibit trends which are linear functions of core size. A neutron drip-line prediction is compared against current models. By considering the possibility of an alpha-cluster core, a new ground-state structure grouping scheme is presented; nucleon-nucleon pairing is shown to have a greater role in level filling. This model, referred to as the Alpha-Deuteron-Neutron Model, yields promising first results when considering root-mean-square variances from the AME2012. The beta-decay of the neutron-rich isotope 74Cu has been studied using three high-purity Germanium clover detectors at the Holifield Radioactive Ion Beam Facility at Oak Ridge National Laboratory. A high-resolution mass separator greatly improved the purity of the 74Cu beam by removing isobaric contaminants, thus allowing decay through its isobar chain to the stable 74Ge at the center of the LeRIBSS detector array without any decay chain member dominating. Using coincidence gating techniques, 121 gamma-rays associated with 74Cu were isolated from the collective singles spectrum. Eighty-seven of these were placed in an expanded level scheme, and updated beta-feeding level intensities and log( ft) values are presented based on multiple newly-placed excited states up to 6.8 MeV. The progression of simulated Total Absorption gamma-ray Spectroscopy (TAGS) based on known levels and beta feeding values from previous measurements to this evaluation are presented and demonstrate the need for a TAGS measurement of this isotope to gain a more complete understanding of its decay scheme.

A density-functional theory investigation of 3-nitro-1,2,4-triazole-5-one dimers and crystal

NASA Astrophysics Data System (ADS)

Xiao, He-Ming; Ju, Xue-Hai; Xu, Li-Na; Fang, Guo-Yong

2004-12-01

Density-functional method with different basis sets was applied to the study of the highly efficient and low sensitive explosive 3-nitro-1,2,4-triazole-5-one (NTO) in both gaseous dimer and its bulk state. The binding energies have been corrected for the basis set superposition errors. Six stable dimers (II-VII) were located. The corrected binding energy of the most stable dimer VII is predicted to be -53.66 kJ/mol at the B3LYP/6-311++G** level. It was found that the structures of the more stable dimers (V-VII) are through the hydrogen bonding interaction between the carbonyl oxygen and the azole hydrogen of 3-nitro-1,2,4-triazole-5-one. The changes of Gibbs free energies (ΔG) in the processes from the monomer to the dimers at 298.15 K are 8.51, 0.90, 0.35, -8.74, -10.67, and -11.06 kJ/mol for dimers from II to VII, respectively. Dimers V-VII, possessing cyclic structures, can be spontaneously produced from the isolated monomer at room temperature. The lattice energy is -156.14 kJ/mol, and this value becomes to -150.43 kJ/mol when a 50% correction of the basis set superposition error was adopted. The frontier bands are quite flat. Judged from the value of band gap of 4.0 eV, it may be predicted that 3-nitro-1,2,4-triazole-5-one is an insulator. Most atoms in NTO, with the exception of C5 atom and the nitro atoms, make up the upper valence bands. In contrast, the lower conduction bands mainly consist of the nitro N and O atoms. The population of the C-NO2 bond is much less than those of the other bonds and the detonation may be initiated by the breakdown of this bond.

A density-functional theory investigation of 3-nitro-1,2,4-triazole-5-one dimers and crystal.

PubMed

Xiao, He-Ming; Ju, Xue-Hai; Xu, Li-Na; Fang, Guo-Yong

2004-12-22

Density-functional method with different basis sets was applied to the study of the highly efficient and low sensitive explosive 3-nitro-1,2,4-triazole-5-one (NTO) in both gaseous dimer and its bulk state. The binding energies have been corrected for the basis set superposition errors. Six stable dimers (II-VII) were located. The corrected binding energy of the most stable dimer VII is predicted to be -53.66 kJ/mol at the B3LYP/6-311++G(**) level. It was found that the structures of the more stable dimers (V-VII) are through the hydrogen bonding interaction between the carbonyl oxygen and the azole hydrogen of 3-nitro-1,2,4-triazole-5-one. The changes of Gibbs free energies (DeltaG) in the processes from the monomer to the dimers at 298.15 K are 8.51, 0.90, 0.35, -8.74, -10.67, and -11.06 kJ/mol for dimers from II to VII, respectively. Dimers V-VII, possessing cyclic structures, can be spontaneously produced from the isolated monomer at room temperature. The lattice energy is -156.14 kJ/mol, and this value becomes to -150.43 kJ/mol when a 50% correction of the basis set superposition error was adopted. The frontier bands are quite flat. Judged from the value of band gap of 4.0 eV, it may be predicted that 3-nitro-1,2,4-triazole-5-one is an insulator. Most atoms in NTO, with the exception of C(5) atom and the nitro atoms, make up the upper valence bands. In contrast, the lower conduction bands mainly consist of the nitro N and O atoms. The population of the C-NO(2) bond is much less than those of the other bonds and the detonation may be initiated by the breakdown of this bond. (c) 2004 American Institute of Physics.

Role of promoter DNA sequence variations on the binding of EGR1 transcription factor.

PubMed

Mikles, David C; Schuchardt, Brett J; Bhat, Vikas; McDonald, Caleb B; Farooq, Amjad

2014-05-01

In response to a wide variety of stimuli such as growth factors and hormones, EGR1 transcription factor is rapidly induced and immediately exerts downstream effects central to the maintenance of cellular homeostasis. Herein, our biophysical analysis reveals that DNA sequence variations within the target gene promoters tightly modulate the energetics of binding of EGR1 and that nucleotide substitutions at certain positions are much more detrimental to EGR1-DNA interaction than others. Importantly, the reduction in binding affinity poorly correlates with the loss of enthalpy and gain of entropy-a trend indicative of a complex interplay between underlying thermodynamic factors due to the differential role of water solvent upon nucleotide substitution. We also provide a rationale for the physical basis of the effect of nucleotide substitutions on the EGR1-DNA interaction at atomic level. Taken together, our study bears important implications on understanding the molecular determinants of a key protein-DNA interaction at the cross-roads of human health and disease. Copyright © 2014 Elsevier Inc. All rights reserved.

Zebavidin - An Avidin-Like Protein from Zebrafish

PubMed Central

Taskinen, Barbara; Zmurko, Joanna; Ojanen, Markus; Kukkurainen, Sampo; Parthiban, Marimuthu; Määttä, Juha A. E.; Leppiniemi, Jenni; Jänis, Janne; Parikka, Mataleena; Turpeinen, Hannu; Rämet, Mika; Pesu, Marko; Johnson, Mark S.; Kulomaa, Markku S.; Airenne, Tomi T.; Hytönen, Vesa P.

2013-01-01

The avidin protein family members are well known for their high affinity towards D-biotin and high structural stability. These properties make avidins valuable tools for a wide range of biotechnology applications. We have identified a new member of the avidin family in the zebrafish (Danio rerio) genome, hereafter called zebavidin. The protein is highly expressed in the gonads of both male and female zebrafish and in the gills of male fish, but our data suggest that zebavidin is not crucial for the developing embryo. Biophysical and structural characterisation of zebavidin revealed distinct properties not found in any previously characterised avidins. Gel filtration chromatography and native mass spectrometry suggest that the protein forms dimers in the absence of biotin at low ionic strength, but assembles into tetramers upon binding biotin. Ligand binding was analysed using radioactive and fluorescently labelled biotin and isothermal titration calorimetry. Moreover, the crystal structure of zebavidin in complex with biotin was solved at 2.4 Å resolution and unveiled unique ligand binding and subunit interface architectures; the atomic-level details support our physicochemical observations. PMID:24204770

Cs 62 DJ Rydberg-atom macrodimers formed by long-range multipole interaction

NASA Astrophysics Data System (ADS)

Han, Xiaoxuan; Bai, Suying; Jiao, Yuechun; Hao, Liping; Xue, Yongmei; Zhao, Jianming; Jia, Suotang; Raithel, Georg

2018-03-01

Long-range macrodimers formed by D -state cesium Rydberg atoms are studied in experiments and calculations. Cesium [62DJ]2 Rydberg-atom macrodimers, bonded via long-range multipole interaction, are prepared by two-color photoassociation in a cesium atom trap. The first color (pulse A) resonantly excites seed Rydberg atoms, while the second (pulse B, detuned by the molecular binding energy) resonantly excites the Rydberg-atom macrodimers below the [62DJ]2 asymptotes. The molecules are measured by extraction of autoionization products and Rydberg-atom electric-field ionization, and ion detection. Molecular spectra are compared with calculations of adiabatic molecular potentials. From the dependence of the molecular signal on the detection delay time, the lifetime of the molecules is estimated to be 3 -6 μ s .

Predicting Ligand Binding Sites on Protein Surfaces by 3-Dimensional Probability Density Distributions of Interacting Atoms

PubMed Central

Jian, Jhih-Wei; Elumalai, Pavadai; Pitti, Thejkiran; Wu, Chih Yuan; Tsai, Keng-Chang; Chang, Jeng-Yih; Peng, Hung-Pin; Yang, An-Suei

2016-01-01

Predicting ligand binding sites (LBSs) on protein structures, which are obtained either from experimental or computational methods, is a useful first step in functional annotation or structure-based drug design for the protein structures. In this work, the structure-based machine learning algorithm ISMBLab-LIG was developed to predict LBSs on protein surfaces with input attributes derived from the three-dimensional probability density maps of interacting atoms, which were reconstructed on the query protein surfaces and were relatively insensitive to local conformational variations of the tentative ligand binding sites. The prediction accuracy of the ISMBLab-LIG predictors is comparable to that of the best LBS predictors benchmarked on several well-established testing datasets. More importantly, the ISMBLab-LIG algorithm has substantial tolerance to the prediction uncertainties of computationally derived protein structure models. As such, the method is particularly useful for predicting LBSs not only on experimental protein structures without known LBS templates in the database but also on computationally predicted model protein structures with structural uncertainties in the tentative ligand binding sites. PMID:27513851

Entropy in bimolecular simulations: A comprehensive review of atomic fluctuations-based methods.

PubMed

Kassem, Summer; Ahmed, Marawan; El-Sheikh, Salah; Barakat, Khaled H

2015-11-01

Entropy of binding constitutes a major, and in many cases a detrimental, component of the binding affinity in biomolecular interactions. While the enthalpic part of the binding free energy is easier to calculate, estimating the entropy of binding is further more complicated. A precise evaluation of entropy requires a comprehensive exploration of the complete phase space of the interacting entities. As this task is extremely hard to accomplish in the context of conventional molecular simulations, calculating entropy has involved many approximations. Most of these golden standard methods focused on developing a reliable estimation of the conformational part of the entropy. Here, we review these methods with a particular emphasis on the different techniques that extract entropy from atomic fluctuations. The theoretical formalisms behind each method is explained highlighting its strengths as well as its limitations, followed by a description of a number of case studies for each method. We hope that this brief, yet comprehensive, review provides a useful tool to understand these methods and realize the practical issues that may arise in such calculations. Copyright © 2015 Elsevier Inc. All rights reserved.

Self-Consistent Charge Density Functional Tight-Binding Study of Poly(3,4-ethylenedioxythiophene): Poly(styrenesulfonate) Ammonia Gas Sensor.

PubMed

Marutaphan, Ampaiwan; Seekaew, Yotsarayuth; Wongchoosuk, Chatchawal

2017-12-01

Geometric and electronic properties of 3,4-ethylenedioxythiophene (EDOT), styrene sulfonate (SS), and EDOT: SS oligomers up to 10 repeating units were studied by the self-consistent charge density functional tight-binding (SCC-DFTB) method. An application of PEDOT:PSS for ammonia (NH 3 ) detection was highlighted and investigated both experimentally and theoretically. The results showed an important role of H-bonds in EDOT:SS oligomers complex conformation. Electrical conductivity of EDOT increased with increasing oligomers and doping SS due to enhancement of π conjugation. Printed PEDOT:PSS gas sensor exhibited relatively high response and selectivity to NH 3 . The SCC-DFTB calculation suggested domination of direct charge transfer process in changing of PEDOT:PSS conductivity upon NH 3 exposure at room temperature. The NH 3 molecules preferred to bind with PEDOT:PSS via physisorption. The most favorable adsorption site for PEDOT:PSS-NH 3 interaction was found to be at the nitrogen atom of NH 3 and hydrogen atoms of SS with an average optimal binding distance of 2.00 Å.

Solution and fluorescence properties of symmetric dipicolylamine-containing dichlorofluorescein-based Zn2+ sensors.

PubMed

Wong, Brian A; Friedle, Simone; Lippard, Stephen J

2009-05-27

The mechanism by which dipicolylamine (DPA) chelate-appended fluorophores respond to zinc was investigated by the synthesis and study of five new analogues of the 2',7'-dichlorofluorescein-based Zn(2+) sensor Zinpyr-1 (ZP1). With the use of absorption and emission spectroscopy in combination with potentiometric titrations, a detailed molecular picture has emerged of the Zn(2+) and H(+) binding properties of the ZP1 family of sensors. The two separate N(3)O donor atom sets on ZP1 converge to form binding pockets in which all four heteroatoms participate in coordination to either Zn(2+) or protons. The position of the pyridyl group nitrogen atom, 2-pyridyl or 4-pyridyl, has a large impact on the fluorescence response of the dyes to protons despite relatively small changes in pK(a) values. The fluorescence quenching effects of such multifunctional electron-donating units are often taken as a whole. Despite the structural complexity of ZP1, however, we provide evidence that the pyridyl arms of the DPA appendages participate in the quenching process, in addition to the contribution from the tertiary nitrogen amine atom. Potentiometric titrations reveal ZP1 dissociation constants (K(d)) for Zn(2+) of 0.04 pM and 1.2 nM for binding to the first and second binding pockets of the ligand, respectively, the second of which correlates with the value observed by fluorescence titration. This result demonstrates that both binding pockets of this symmetric, ditopic sensor need to be occupied in order for full fluorescence turn-on to be achieved. These results have significant implications for the design and implementation of fluorescent sensors for studies of mobile zinc ions in biology.

Crown ethers in graphene

DOE PAGES

Guo, Junjie; Lee, Jaekwang; Contescu, Cristian I.; ...

2014-11-13

Crown ethers, introduced by Pedersen1, are at their most basic level neutral rings constructed of oxygen atoms linked by two- or three-carbon chains. They have attracted special attention for their ability to selectively incorporate various atoms2 or molecules within the cavity formed by the ring3-6. This property has led to the use of crown ethers and their compounds in a wide range of chemical and biological applications7,8. However, crown ethers are typically highly flexible, frustrating efforts to rigidify them for many uses that demand higher binding affinity and selectivity9,10. In this Letter, we report atomic-resolution images of the same basicmore » structures of the original crown ethers embedded in graphene. This arrangement constrains the crown ethers to be rigid and planar and thus uniquely suited for the many applications that crown ethers are known for. First-principles calculations show that the close similarity of the structures seen in graphene with those of crown ether molecules also extends to their selectivity towards specific metal cations depending on the ring size. Atoms (or molecules) incorporated within the crown ethers in graphene offer a simple environment that can be easily and systematically probed and modeled. Thus, we expect that this discovery will introduce a new wave of investigations and applications of chemically functionalized graphene.« less

Substrate effect on the growth of Sn thin films

NASA Astrophysics Data System (ADS)

Chakraborty, Suvankar; Menon, Krishnakumar S. R.

2018-05-01

Growth of tin (Sn) on Ag(001), Ag(111) and W(110) substrate has been studied at elevated temperatures (473 K) using x-ray photoemission spectroscopy (XPS) and low energy electron diffraction (LEED). For Sn growth on silver substrates, it is noticed that both Sn 3d and Ag 3d core-level spectra shift in the higher binding energy direction due to the formation of surface alloy with the substrate. In both cases, surface alloy finally transforms into bulk alloy finally reaching bulk Sn value. For Sn growth on W(110) only Sn 3d core-level spectra shift in the higher binding energy direction due to surface core-level effect whereas no shift for tungsten core-level was noticed confirming no alloy formation. Sn is incorporated into the surface of substrate silver layer by removing every alternate or every third silver atoms to relieve the surface tensile stress as confirmed by LEED. On the other hand, tungsten being hard, Sn forms an overlayer structure by sitting in different energetically available positions rather than forming an alloy as energetically also it is not possible. Sn forms alloy with soft substrate silver and form overlayer films with tungsten. These studies are important in understanding the growth mechanism of Sn films on metal substrates.

Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Hongmin; Astrof, Nathan S.; Liu, Jin-Huan

2009-09-15

Volatile anesthetics (VAs), such as isoflurane, induce a general anesthetic state by binding to specific targets (i.e., ion channels) in the central nervous system (CNS). Simultaneously, VAs modulate immune functions, possibly via direct interaction with alternative targets on leukocytes. One such target, the integrin lymphocyte function-associated antigen-1 (LFA-1), has been shown previously to be inhibited by isoflurane. A better understanding of the mechanism by which isoflurane alters protein function requires the detailed information about the drug-protein interaction at an atomic level. Here, we describe the crystal structure of the LFA-1 ligand-binding domain (I domain) in complex with isoflurane at 1.6more » {angstrom}. We discovered that isoflurane binds to an allosteric cavity previously implicated as critical for the transition of LFA-1 from the low- to the high-affinity state. The isoflurane binding site in the I domain involves an array of amphiphilic interactions, thereby resembling a 'common anesthetic binding motif' previously predicted for authentic VA binding sites. These results suggest that the allosteric modulation of protein function by isoflurane, as demonstrated for the integrin LFA-1, might represent a unified mechanism shared by the interactions of volatile anesthetics with targets in the CNS. Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems.« less

Structural, energetic, spectroscopic and QTAIM analyses of cation-π interactions involving mono- and bi-cyclic ring fused benzene systems.

PubMed

Hassan, Ayorinde; Dinadayalane, Tandabany C; Grabowski, Sławomir J; Leszczynski, Jerzy

2013-12-28

The effect of increasing the number of monocyclic six-membered rings or bicyclic rings of bicyclo[2.1.1]hexenyl fused to benzene on cation-π interactions involving alkali metal ions (Li(+), Na(+), and K(+)) has been investigated. The binding energy data at the B3LYP/6-311+G(2d,2p) level clearly indicate that the binding affinity of the metal ion with benzene is enhanced by increasing the number of rings fused irrespective of a monocyclic or a bicyclic ring. Calculated binding energies are in good agreement with the available experimental results. The binding strength of cations with ligands decreases in the order Li(+) > Na(+) > K(+). Our study establishes that trisannelation of bicyclo[2.1.1]hexene to benzene facilitates a very strong interaction between benzene and cations. Infrared (IR) frequencies and nuclear magnetic resonance (NMR) chemical shifts are shown to be valuable in characterizing cation-π interactions. The C-C bonds of the central six-membered rings are weakened due to metal ion binding. Based on the Quantum Theory of Atoms in Molecules (QTAIM), we have observed the presence of stabilizing H∙∙∙H interactions in two of the considered systems as opposed to the frequent description of these interactions as non-bonded repulsive interactions. Alkali metal ion binding with those two ligands slightly reduces the strength of such H∙∙∙H interactions.

First-principle calculation of core level binding energies of Li{sub x}PO{sub y}N{sub z} solid electrolyte

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guille, Émilie; Vallverdu, Germain, E-mail: germain.vallverdu@univ-pau.fr; Baraille, Isabelle

2014-12-28

We present first-principle calculations of core-level binding energies for the study of insulating, bulk phase, compounds, based on the Slater-Janak transition state model. Those calculations were performed in order to find a reliable model of the amorphous Li{sub x}PO{sub y}N{sub z} solid electrolyte which is able to reproduce its electronic properties gathered from X-ray photoemission spectroscopy (XPS) experiments. As a starting point, Li{sub 2}PO{sub 2}N models were investigated. These models, proposed by Du et al. on the basis of thermodynamics and vibrational properties, were the first structural models of Li{sub x}PO{sub y}N{sub z}. Thanks to chemical and structural modifications appliedmore » to Li{sub 2}PO{sub 2}N structures, which allow to demonstrate the relevance of our computational approach, we raise an issue concerning the possibility of encountering a non-bridging kind of nitrogen atoms (=N{sup −}) in Li{sub x}PO{sub y}N{sub z} compounds.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Wenjie; Zhang, Honghu; Feng, Shuren

Surface-sensitive X-ray scattering and spectroscopy techniques reveal significant adsorption of iron ions and iron-hydroxide (Fe(III)) complexes to a charge-neutral zwitterionic template of phosphatidylcholine (PC). The PC template is formed by a Langmuir monolayer of dipalmitoyl-PC (DPPC) that is spread on the surface of 2 to 40 μM FeCl 3 solutions at physiological levels of KCl (100 mM). At 40 μM of Fe(III) as many as ~3 iron atoms are associated with each PC group. Grazing incidence X-ray diffraction measurements indicate a significant disruption in the in-plane ordering of DPPC molecules upon iron adsorption. The binding of iron-hydroxide complexes to amore » neutral PC surface is yet another example of nonelectrostatic, presumably covalent bonding to a charge-neutral organic template. Furthermore, the strong binding and the disruption of in-plane lipid structure has biological implications on the integrity of PC-derived lipid membranes, including those based on sphingomyelin.« less

The structures of bare and deuterated Co{sub 19}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parks, E.K.; Riley, S.J.

1997-07-01

The structures of bare Co{sub 19} and deuterated Co{sub 19}D{sub m} clusters are examined by the chemical probe method, and earlier assignments of bare Co{sub 19} as an fcc octahedron are reconsidered. New experimental measurements of the reactivity of Co{sub 19} with ammonia, nitrogen, and deuterium are presented, and together with earlier measurements of the reactivity with water suggest that bare Co{sub 19} has an hcp structure (D{sub 3h} symmetry). The adsorption of deuterium on Co{sub 19} is found to proceed in steps, leading to successive saturation levels at Co{sub 19}D{sub 4}, Co{sub 19}D{sub 14}, and Co{sub 19}D{sub 18}. Usingmore » binding rules derived from earlier studies of larger cobalt and nickel clusters, possible D-atom binding sites on Co{sub 19}D{sub m} (both fcc and hcp) are proposed.« less

Ligand Binding: Molecular Mechanics Calculation of the Streptavidin-Biotin Rupture Force

NASA Astrophysics Data System (ADS)

Grubmuller, Helmut; Heymann, Berthold; Tavan, Paul

1996-02-01

The force required to rupture the streptavidin-biotin complex was calculated here by computer simulations. The computed force agrees well with that obtained by recent single molecule atomic force microscope experiments. These simulations suggest a detailed multiple-pathway rupture mechanism involving five major unbinding steps. Binding forces and specificity are attributed to a hydrogen bond network between the biotin ligand and residues within the binding pocket of streptavidin. During rupture, additional water bridges substantially enhance the stability of the complex and even dominate the binding inter-actions. In contrast, steric restraints do not appear to contribute to the binding forces, although conformational motions were observed.

Receptor interactrions of imidazolines. VI. Significance of carbon bridge separating phenyl and imidazoline rings of tolazoline-like alpha adrenergic imidazolines.

PubMed

Ruffolo, R R; Yaden, E L; Waddell, J E; Dillard, R D

1980-09-01

The pharmacological significance of the carbon bridge separating the imidazoline and phenyl rings of tolazoline-like alpha adrenergic imidazolines has been investigated. Extending the carbon bridge to two carbon atoms, or deleting the carbon bridge, lowers affinity of the imidazolines for the alpha receptor and markedly decreases or abolishes efficacy (i.e., agonist activity), suggesting that a single carbon atome optimallyu separates the phenyl and imidazoline rings. Although one carbon is optimal for alpha adrenergic activity, this particular atom does not appear to be essential since nitrogen may substitute for carbon with no marked or consistent changes observed in affinity or efficacy. Hydroxylation of the carbon bridge decreases affinity for the receptor approximately 10-fold but does not alter efficacy, whereas a similar substitution made in the norepinephrine-series of phenethylamines markedly increases affinity (Patil et al., 1974). With both the imidazolines and phenethylamines, this carbon atom may stereoselectively influence binding to the receptor. These results suggest that the carbon atom bridging the phenyl and imidazoline rings of tolazoline-like imidazolines serves only to provide optimal separation between these rings and does not contribute directly to the binding process. It is proposed that alpha adrenergic imidazolines interact differently with the alpha adrenergic receptor than the norepinephrine-like phenethylamines.

Molecular dynamics simulations of apocupredoxins: insights into the formation and stabilization of copper sites under entatic control.

PubMed

Abriata, Luciano A; Vila, Alejandro J; Dal Peraro, Matteo

2014-06-01

Cupredoxins perform copper-mediated long-range electron transfer (ET) in biological systems. Their copper-binding sites have evolved to force copper ions into ET-competent systems with decreased reorganization energy, increased reduction potential, and a distinct electronic structure compared with those of non-ET-competent copper complexes. The entatic or rack-induced state hypothesis explains these special properties in terms of the strain that the protein matrix exerts on the metal ions. This idea is supported by X-ray structures of apocupredoxins displaying "closed" arrangements of the copper ligands like those observed in the holoproteins; however, it implies completely buried copper-binding atoms, conflicting with the notion that they must be exposed for copper loading. On the other hand, a recent work based on NMR showed that the copper-binding regions of apocupredoxins are flexible in solution. We have explored five cupredoxins in their "closed" apo forms through molecular dynamics simulations. We observed that prearranged ligand conformations are not stable as the X-ray data suggest, although they do form part of the dynamic landscape of the apoproteins. This translates into variable flexibility of the copper-binding regions within a rigid fold, accompanied by fluctuations of the hydrogen bonds around the copper ligands. Major conformations with solvent-exposed copper-binding atoms could allow initial binding of the copper ions. An eventual subsequent incursion to the closed state would result in binding of the remaining ligands, trapping the closed conformation thanks to the additional binding energy and the fastening of noncovalent interactions that make up the rack.

Multiple binding modes for palmitate to barley lipid transfer protein facilitated by the presence of proline 12.

PubMed

Smith, Lorna J; Gunsteren, Wilfred F Van; Allison, Jane R

2013-01-01

Molecular dynamics simulations have been used to characterise the binding of the fatty acid ligand palmitate in the barley lipid transfer protein 1 (LTP) internal cavity. Two different palmitate binding modes (1 and 2), with similar protein-ligand interaction energies, have been identified using a variety of simulation strategies. These strategies include applying experimental protein-ligand atom-atom distance restraints during the simulation, or protonating the palmitate ligand, or using the vacuum GROMOS 54B7 force-field parameter set for the ligand during the initial stages of the simulations. In both the binding modes identified the palmitate carboxylate head group hydrogen bonds with main chain amide groups in helix A, residues 4 to 19, of the protein. In binding mode 1 the hydrogen bonds are to Lys 11, Cys 13, and Leu 14 and in binding mode 2 to Thr 15, Tyr 16, Val 17, Ser 24 and also to the OH of Thr 15. In both cases palmitate binding exploits irregularity of the intrahelical hydrogen-bonding pattern in helix A of barley LTP due to the presence of Pro 12. Simulations of two variants of barley LTP, namely the single mutant Pro12Val and the double mutant Pro12Val Pro70Val, show that Pro 12 is required for persistent palmitate binding in the LTP cavity. Overall, the work identifies key MD simulation approaches for characterizing the details of protein-ligand interactions in complexes where NMR data provide insufficient restraints. Copyright © 2012 The Protein Society.

Crystallization of Mitochondrial Respiratory Complex II from Chicken Heart: a Membrane Protein Complex Diffracting to 2.0 Å.

PubMed Central

Huang, Li-shar; Borders, Toni M.; Shen, John T.; Wang, Chung-Jen; Berry, Edward

2006-01-01

Synopsis A multi-subunit mitochondrial membrane protein complex involved in the Krebs Cycle and respiratory chain has been crystallized in a form suitable for near-atomic resolution structure determination. A procedure is presented for preparation of diffraction-quality crystals of a vertebrate mitochondrial respiratory Complex II. The crystals have the potential to diffract to at least 2.0 Å with optimization of post-crystal-growth treatment and cryoprotection. This should allow determination of the structure of this important and medically relevant membrane protein complex at near-atomic resolution and provide great detail of the mode of binding of substrates and inhibitors at the two substrate-binding sites. PMID:15805592

Molecular Basis for Differential Anion Binding and Proton Coupling in the Cl−/H+ Exchanger ClC-ec1

PubMed Central

Jiang, Tao; Han, Wei; Maduke, Merritt; Tajkhorshid, Emad

2016-01-01

Cl−/H+ transporters of the CLC superfamily form a ubiquitous class of membrane proteins that catalyze stoichiometrically coupled exchange of Cl− and H+ across biological membranes. CLC transporters exchange H+ for halides and certain polyatomic anions, but exclude cations, F−, and larger physiological anions, such as PO43− and SO42−. Despite comparable transport rates of different anions, the H+ coupling in CLC transporters varies significantly depending on the chemical nature of the transported anion. Although the molecular mechanism of exchange remains unknown, studies on bacterial ClC-ec1 transporter revealed that Cl− binding to the central anion-binding site (Scen) is crucial for the anion-coupled H+ transport. Here, we show that Cl−, F−, NO3−, and SCN− display distinct binding coordinations at the Scen site and are hydrated in different manners. Consistent with the observation of differential bindings, ClC-ec1 exhibits markedly variable ability to support the formation of the transient water wires, which are necessary to support the connection of the two H+ transfer sites (Gluin and Gluex), in the presence of different anions. While continuous water wires are frequently observed in the presence of physiologically transported Cl−, binding of F− or NO3− leads to the formation of pseudo-water-wires that are substantially different from the wires formed with Cl−. Binding of SCN−, however, eliminates the water wires altogether. These findings provide structural details of anion binding in ClC-ec1 and reveal a putative atomic-level mechanism for the decoupling of H+ transport to the transport of anions other than Cl−. PMID:26880377

Mechanistic Insights into the Allosteric Modulation of Opioid Receptors by Sodium Ions

PubMed Central

2015-01-01

The idea of sodium ions altering G-protein-coupled receptor (GPCR) ligand binding and signaling was first suggested for opioid receptors (ORs) in the 1970s and subsequently extended to other GPCRs. Recently published ultra-high-resolution crystal structures of GPCRs, including that of the δ-OR subtype, have started to shed light on the mechanism underlying sodium control in GPCR signaling by revealing details of the sodium binding site. Whether sodium accesses different receptor subtypes from the extra- or intracellular sides, following similar or different pathways, is still an open question. Earlier experiments in brain homogenates suggested a differential sodium regulation of ligand binding to the three major OR subtypes, in spite of their high degree of sequence similarity. Intrigued by this possibility, we explored the dynamic nature of sodium binding to δ-OR, μ-OR, and κ-OR by means of microsecond-scale, all-atom molecular dynamics (MD) simulations. Rapid sodium permeation was observed exclusively from the extracellular milieu, and following similar binding pathways in all three ligand-free OR systems, notwithstanding extra densities of sodium observed near nonconserved residues of κ-OR and δ-OR, but not in μ-OR. We speculate that these differences may be responsible for the differential increase in antagonist binding affinity of μ-OR by sodium resulting from specific ligand binding experiments in transfected cells. On the other hand, sodium reduced the level of binding of subtype-specific agonists to all OR subtypes. Additional biased and unbiased MD simulations were conducted using the δ-OR ultra-high-resolution crystal structure as a model system to provide a mechanistic explanation for this experimental observation. PMID:25073009

Mechanistic insights into the allosteric modulation of opioid receptors by sodium ions.

PubMed

Shang, Yi; LeRouzic, Valerie; Schneider, Sebastian; Bisignano, Paola; Pasternak, Gavril W; Filizola, Marta

2014-08-12

The idea of sodium ions altering G-protein-coupled receptor (GPCR) ligand binding and signaling was first suggested for opioid receptors (ORs) in the 1970s and subsequently extended to other GPCRs. Recently published ultra-high-resolution crystal structures of GPCRs, including that of the δ-OR subtype, have started to shed light on the mechanism underlying sodium control in GPCR signaling by revealing details of the sodium binding site. Whether sodium accesses different receptor subtypes from the extra- or intracellular sides, following similar or different pathways, is still an open question. Earlier experiments in brain homogenates suggested a differential sodium regulation of ligand binding to the three major OR subtypes, in spite of their high degree of sequence similarity. Intrigued by this possibility, we explored the dynamic nature of sodium binding to δ-OR, μ-OR, and κ-OR by means of microsecond-scale, all-atom molecular dynamics (MD) simulations. Rapid sodium permeation was observed exclusively from the extracellular milieu, and following similar binding pathways in all three ligand-free OR systems, notwithstanding extra densities of sodium observed near nonconserved residues of κ-OR and δ-OR, but not in μ-OR. We speculate that these differences may be responsible for the differential increase in antagonist binding affinity of μ-OR by sodium resulting from specific ligand binding experiments in transfected cells. On the other hand, sodium reduced the level of binding of subtype-specific agonists to all OR subtypes. Additional biased and unbiased MD simulations were conducted using the δ-OR ultra-high-resolution crystal structure as a model system to provide a mechanistic explanation for this experimental observation.

Multi-scale predictive modeling of nano-material and realistic electron devices

NASA Astrophysics Data System (ADS)

Palaria, Amritanshu

Among the challenges faced in further miniaturization of electronic devices, heavy influence of the detailed atomic configuration of the material(s) involved, which often differs significantly from that of the bulk material(s), is prominent. Device design has therefore become highly interrelated with material engineering at the atomic level. This thesis aims at outlining, with examples, a multi-scale simulation procedure that allows one to integrate material and device aspects of nano-electronic design to predict behavior of novel devices with novel material. This is followed in four parts: (1) An approach that combines a higher time scale reactive force field analysis with density functional theory to predict structure of new material is demonstrated for the first time for nanowires. Novel stable structures for very small diameter silicon nanowires are predicted. (2) Density functional theory is used to show that the new nanowire structures derived in 1 above have properties different from diamond core wires even though the surface bonds in some may be similar to the surface of bulk silicon. (3) Electronic structure of relatively large-scale germanium sections of realistically strained Si/strained Ge/ strained Si nanowire heterostructures is computed using empirical tight binding and it is shown that the average non-homogeneous strain in these structures drives their interesting non-conventional electronic characteristics such as hole effective masses which decrease as the wire cross-section is reduced. (4) It is shown that tight binding, though empirical in nature, is not necessarily limited to the material and atomic structure for which the parameters have been empirically derived, but that simple changes may adapt the derived parameters to new bond environments. Si (100) surface electronic structure is obtained from bulk Si parameters.

Three-dimensional structure of cofilin bound to monomeric actin derived by structural mass spectrometry data

PubMed Central

Kamal, J. K. Amisha; Benchaar, Sabrina A.; Takamoto, Keiji; Reisler, Emil; Chance, Mark R.

2007-01-01

The cytoskeletal protein, actin, has its structure and function regulated by cofilin. In the absence of an atomic resolution structure for the actin/cofilin complex, the mechanism of cofilin regulation is poorly understood. Theoretical studies based on the similarities of cofilin and gelsolin segment 1 proposed the cleft between subdomains 1 and 3 in actin as the cofilin binding site. We used radiolytic protein footprinting with mass spectrometry and molecular modeling to provide an atomic model of how cofilin binds to monomeric actin. Footprinting data suggest that cofilin binds to the cleft between subdomains 1 and 2 in actin and that cofilin induces further closure of the actin nucleotide cleft. Site-specific fluorescence data confirm these results. The model identifies key ionic and hydrophobic interactions at the binding interface, including hydrogen-bonding between His-87 of actin to Ser-89 of cofilin that may control the charge dependence of cofilin binding. This model and its implications fill an especially important niche in the actin field, owing to the fact that ongoing crystallization efforts of the actin/cofilin complex have so far failed. This 3D binary complex structure is derived from a combination of solution footprinting data and computational approaches and outlines a general method for determining the structure of such complexes. PMID:17470807

Toward an Experimental Quantum Chemistry: Exploring a New Energy Partitioning.

PubMed

Rahm, Martin; Hoffmann, Roald

2015-08-19

Following the work of L. C. Allen, this work begins by relating the central chemical concept of electronegativity with the average binding energy of electrons in a system. The average electron binding energy, χ̅, is in principle accessible from experiment, through photoelectron and X-ray spectroscopy. It can also be estimated theoretically. χ̅ has a rigorous and understandable connection to the total energy. That connection defines a new kind of energy decomposition scheme. The changing total energy in a reaction has three primary contributions to it: the average electron binding energy, the nuclear-nuclear repulsion, and multielectron interactions. This partitioning allows one to gain insight into the predominant factors behind a particular energetic preference. We can conclude whether an energy change in a transformation is favored or resisted by collective changes to the binding energy of electrons, the movement of nuclei, or multielectron interactions. For example, in the classical formation of H2 from atoms, orbital interactions dominate nearly canceling nuclear-nuclear repulsion and two-electron interactions. While in electron attachment to an H atom, the multielectron interactions drive the reaction. Looking at the balance of average electron binding energy, multielectron, and nuclear-nuclear contributions one can judge when more traditional electronegativity arguments can be justifiably invoked in the rationalization of a particular chemical event.

Crystal Structure of Calmodulin Binding Domain of Orai1 in Complex with Ca2+•Calmodulin Displays a Unique Binding Mode*

PubMed Central

Liu, Yanshun; Zheng, Xunhai; Mueller, Geoffrey A.; Sobhany, Mack; DeRose, Eugene F.; Zhang, Yingpei; London, Robert E.; Birnbaumer, Lutz

2012-01-01

Orai1 is a plasma membrane protein that in its tetrameric form is responsible for calcium influx from the extracellular environment into the cytosol in response to interaction with the Ca2+-depletion sensor STIM1. This is followed by a fast Ca2+·calmodulin (CaM)-dependent inhibition, resulting from CaM binding to an Orai1 region called the calmodulin binding domain (CMBD). The interaction between Orai1 and CaM at the atomic level remains unknown. Here, we report the crystal structure of a CaM·Orai1-CMBD complex showing one CMBD bound to the C-terminal lobe of CaM, differing from other CaM-target protein complexes, in which both N- and C-terminal lobes of CaM (CaM-N and CaM-C) are involved in target binding. Orai1-CMBD binds CaM-C mainly through hydrophobic interactions, primarily involving residue Trp76 of Orai1-CMBD, which interacts with the hydrophobic pocket of CaM-C. However, NMR data, isothermal titration calorimetry data, and pulldown assays indicated that CaM-N and CaM-C both can bind Orai1-CMBD, with CaM-N having ∼4 times weaker affinity than CaM-C. Pulldown assays of a Orai1-CMBD(W76E) mutant, gel filtration chromatography data, and NOE signals indicated that CaM-N and CaM-C can each bind one Orai1-CMBD. Thus our studies support an unusual, extended 1:2 binding mode of CaM to Orai1-CMBDs, and quantify the affinity of Orai1 for CaM. We propose a two-step mechanism for CaM-dependent Orai1 inactivation initiated by binding of the C-lobe of CaM to the CMBD of one Orai1 followed by the binding of the N-lobe of CaM to the CMBD of a neighboring Orai1. PMID:23109337

Ultra-cold molecules in an atomic Bose-Einstein condensate

NASA Astrophysics Data System (ADS)

Wynar, Roahn Helden

2000-08-01

This thesis is about photoassociation of Bose-condensed 87Rb. Most importantly we report that state selected 87Rb2 molecules were created at rest in a condensate of 87Rb using two-photon photoassociation. Additionally, we have identified three weakly bound states of the 87Rb2 S+u3 , potential for the |1, -1> + |1, - 1> collisional channel. The binding energies of these states are 529.4 +/- .07, 636.0094 +/- .0012, and 24.24 +/- .01 MHz respectively. We have also carried out a detailed study of the density dependence of the shift and width of the two-photon lineshape. This shift and width is modeled using the theory of Bohn and Julienne [34] and in addition to the precise measurement of binding energy we also report the first measurement of an atom molecule scattering length, aam, which we conclude is -180 +/- 150 a0, and the inelastic collision rate, Kinel < 8 × 10-11 cm-3/s. Stimulated Raman free bound coupling in an atomic Bose- Einstein condensate may lead to the formation of a molecular condensate. In order to evaluate this possibility we present a many-body quantum mean field theory of a Bose-Einstein condensate that includes a density dependent coherent coupling between atoms and molecules. This theory yields two coupled equations, one for the evolution of atomic condensate amplitude and one for the evolution of molecular condensate amplitude. The nature of the atomic-molecular condensate evolution is shown to depend on six, model parameters including the coherent coupling, given by cn . The other five parameters can be interpreted as light-shifts and incoherent loss rates. We present a calculation intended to estimate the values of these six parameters for the 87Rb - 87Rb 2 system. Based on the results of this calculation we identify two locations in the 87Rb2 spectrum where coherent transfer of population from atomic condensate to molecular condensate is plausible. Finally, we examine the credibility of the theoretical model used to estimate the six parameters used by the mean field theory. By comparing the measured Stark shifts of two-color resonances with predictions based on our theoretical model we conclude that the model is satisfactory for the v = 37 level of the S+u3 potential. This work also describes the experimental details of stabilizing a Coherent 899-01 Ti:Saphire laser and the experimental methods important to executing photoassociation in a time-averaged-orbiting potential (TOP) trap.

Stabilized sulfur binding using activated fillers

DOEpatents

Kalb, Paul D.; Vagin, Vyacheslav P.; Vagin, Sergey P.

2015-07-21

A method of making a stable, sulfur binding composite comprising impregnating a solid aggregate with an organic modifier comprising unsaturated hydrocarbons with at least one double or triple covalent bond between adjacent carbon atoms to create a modifier-impregnated aggregate; heating and drying the modifier-impregnated aggregate to activate the surface of the modifier-impregnated aggregate for reaction with sulfur.

GalaxyDock BP2 score: a hybrid scoring function for accurate protein-ligand docking

NASA Astrophysics Data System (ADS)

Baek, Minkyung; Shin, Woong-Hee; Chung, Hwan Won; Seok, Chaok

2017-07-01

Protein-ligand docking is a useful tool for providing atomic-level understanding of protein functions in nature and design principles for artificial ligands or proteins with desired properties. The ability to identify the true binding pose of a ligand to a target protein among numerous possible candidate poses is an essential requirement for successful protein-ligand docking. Many previously developed docking scoring functions were trained to reproduce experimental binding affinities and were also used for scoring binding poses. However, in this study, we developed a new docking scoring function, called GalaxyDock BP2 Score, by directly training the scoring power of binding poses. This function is a hybrid of physics-based, empirical, and knowledge-based score terms that are balanced to strengthen the advantages of each component. The performance of the new scoring function exhibits significant improvement over existing scoring functions in decoy pose discrimination tests. In addition, when the score is used with the GalaxyDock2 protein-ligand docking program, it outperformed other state-of-the-art docking programs in docking tests on the Astex diverse set, the Cross2009 benchmark set, and the Astex non-native set. GalaxyDock BP2 Score and GalaxyDock2 with this score are freely available at http://galaxy.seoklab.org/softwares/galaxydock.html.

Fragment-based drug discovery and its application to challenging drug targets.

PubMed

Price, Amanda J; Howard, Steven; Cons, Benjamin D

2017-11-08

Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of low molecular weight compounds (fragments). Although fragments bind to proteins with relatively low affinity, they form efficient, high quality binding interactions with the protein architecture as they have to overcome a significant entropy barrier to bind. Of the biophysical methods available for fragment screening, X-ray protein crystallography is one of the most sensitive and least prone to false positives. It also provides detailed structural information of the protein-fragment complex at the atomic level. Fragment-based screening using X-ray crystallography is therefore an efficient method for identifying binding hotspots on proteins, which can then be exploited by chemists and biologists for the discovery of new drugs. The use of FBDD is illustrated here with a recently published case study of a drug discovery programme targeting the challenging protein-protein interaction Kelch-like ECH-associated protein 1:nuclear factor erythroid 2-related factor 2. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Interactions between the antifungal drug myclobutanil and gold and silver nanoparticles in Penicillium digitatum investigated by surface-enhanced Raman scattering.

PubMed

Cho, Eun-Min; Singh, Dheeraj K; Ganbold, Erdene-Ochir; Dembereldorj, Uuriintuya; Jang, Seok-Won; Kim, Doseok; Choo, Jaebum; Kim, Sehun; Lee, Cheol Min; Yang, Sung Ik; Joo, Sang-Woo

2014-01-01

Surface-enhanced Raman scattering (SERS) of an antifungal reagent, myclobutanil (MCB), was performed on Au and Ag nanoparticles (NPs) to estimate the drug-release behaviors in fungal cells. A density functional theory (DFT) calculation was introduced to predict a favorable binding site of MCB to either the Ag or Au atom. Myclobutanil was presumed to bind more strongly to Au than to Ag in their most stable, optimized geometries of the N4 atom in its 1,2,4-triazole unit binding to the metal atom. Strong intensities were observed in the Ag SERS spectra only at acidic pH values, whereas the most prominent peaks in the Au SERS spectra of MCB matched quite well with those of 1,2,4-triazole regardless of pH conditions. The Raman spectral intensities of the MCB-assembled Ag and Au NPs decreased after treatment with either potato dextrose agar (PDA) or glutathione (GSH). Darkfield microscopy and confocal SERS were performed to analyze the MCB-assembled metal NPs inside Penicillium digitatum fungal cells. The results suggested that MCB was released from the metal NPs in the intracellular GSH in the fungi because we observed only fungal cell peaks.

Enhancement of the Stability of Fluorine Atoms on Defective Graphene and at Graphene/Fluorographene Interface.

PubMed

Ao, Zhimin; Jiang, Quanguo; Li, Shuang; Liu, Hao; Peeters, Francois M; Li, Sean; Wang, Guoxiu

2015-09-09

Fluorinated graphene is one of the most important derivatives of graphene and has been found to have great potential in optoelectronic and photonic nanodevices. However, the stability of F atoms on fluorinated graphene under different conditions, which is essential to maintain the desired properties of fluorinated graphene, is still unclear. In this work, we investigate the diffusion of F atoms on pristine graphene, graphene with defects, and at graphene/fluorographene interfaces by using density functional theory calculations. We find that an isolated F atom diffuses easily on graphene, but those F atoms can be localized by inducing vacancies or absorbates in graphene and by creating graphene/fluorographene interfaces, which would strengthen the binding energy of F atoms on graphene and increase the diffusion energy barrier of F atoms remarkably.

IsoCleft Finder – a web-based tool for the detection and analysis of protein binding-site geometric and chemical similarities

PubMed Central

Najmanovich, Rafael

2013-01-01

IsoCleft Finder is a web-based tool for the detection of local geometric and chemical similarities between potential small-molecule binding cavities and a non-redundant dataset of ligand-bound known small-molecule binding-sites. The non-redundant dataset developed as part of this study is composed of 7339 entries representing unique Pfam/PDB-ligand (hetero group code) combinations with known levels of cognate ligand similarity. The query cavity can be uploaded by the user or detected automatically by the system using existing PDB entries as well as user-provided structures in PDB format. In all cases, the user can refine the definition of the cavity interactively via a browser-based Jmol 3D molecular visualization interface. Furthermore, users can restrict the search to a subset of the dataset using a cognate-similarity threshold. Local structural similarities are detected using the IsoCleft software and ranked according to two criteria (number of atoms in common and Tanimoto score of local structural similarity) and the associated Z-score and p-value measures of statistical significance. The results, including predicted ligands, target proteins, similarity scores, number of atoms in common, etc., are shown in a powerful interactive graphical interface. This interface permits the visualization of target ligands superimposed on the query cavity and additionally provides a table of pairwise ligand topological similarities. Similarities between top scoring ligands serve as an additional tool to judge the quality of the results obtained. We present several examples where IsoCleft Finder provides useful functional information. IsoCleft Finder results are complementary to existing approaches for the prediction of protein function from structure, rational drug design and x-ray crystallography. IsoCleft Finder can be found at: http://bcb.med.usherbrooke.ca/isocleftfinder. PMID:24555058

The switching mechanism of the mitochondrial ADP/ATP carrier explored by free-energy landscapes.

PubMed

Pietropaolo, Adriana; Pierri, Ciro Leonardo; Palmieri, Ferdinando; Klingenberg, Martin

2016-06-01

The ADP/ATP carrier (AAC) of mitochondria has been an early example for elucidating the transport mechanism alternating between the external (c-) and internal (m-) states (M. Klingenberg, Biochim. Biophys. Acta 1778 (2008) 1978-2021). An atomic resolution crystal structure of AAC is available only for the c-state featuring a three repeat transmembrane domain structure. Modeling of transport mechanism remained hypothetical for want of an atomic structure of the m-state. Previous molecular dynamics studies simulated the binding of ADP or ATP to the AAC remaining in the c-state. Here, a full description of the AAC switching from the c- to the m-state is reported using well-tempered metadynamics simulations. Free-energy landscapes of the entire translocation from the c- to the m-state, based on the gyration radii of the c- and m-gates and of the center of mass, were generated. The simulations revealed three free-energy basins attributed to the c-, intermediate- and m-states separated by activation barriers. These simulations were performed with the empty and with the ADP- and ATP-loaded AAC as well as with the poorly transported AMP and guanine nucleotides, showing in the free energy landscapes that ADP and ATP lowered the activation free-energy barriers more than the other substrates. Upon binding AMP and guanine nucleotides a deeper free-energy level stabilized the intermediate-state of the AAC2 hampering the transition to the m-state. The structures of the substrate binding sites in the different states are described producing a full picture of the translocation events in the AAC. Copyright © 2016 Elsevier B.V. All rights reserved.

DFT-based molecular modeling and vibrational study of the La(III) complex of 3,3'-(benzylidene)bis(4-hydroxycoumarin).

PubMed

Mihaylov, Tzvetan; Trendafilova, Natasha; Georgieva, Ivelina

2008-05-01

Molecular modeling of the La(III) complex of 3,3'-(benzylidene)bis(4-hydroxycoumarin) (PhDC) was performed using density functional theory (DFT) methods at B3LYP/6-31G(d) and BP86/TZP levels. Both Stuttgart-Dresden effective core potential and ZORA approximation were applied to the La(III) center. The electron density distribution and the nucleophilic centers of the deprotonated ligand PhDC(2-) in a solvent environment were estimated on the basis of Hirshfeld atomic charges, electrostatic potential values at the nuclei, and Nalewajski-Mrozek bond orders. In accordance with the empirical formula La(PhDC)(OH)(H(2)O), a chain structure of the complex was simulated by means of two types of molecular fragment: (1) two La(III) cations bound to one PhDC(2-) ligand, and (2) two PhDC(2-) ligands bound to one La(III) cation. Different orientations of PhDC(2-), OH(-) and H(2)O ligands in the La(III) complexes were investigated using 20 possible [La(PhDC(2-))(2)(OH)(H(2)O)](2-) fragments. Energy calculations predicted that the prism-like structure based on "tail-head" cis-LML2 type binding and stabilized via HO...HOH intramolecular hydrogen bonds is the most probable structure for the La(III) complex. The calculated vibrational spectrum of the lowest energy La(III) model fragment is in very good agreement with the experimental IR spectrum of the complex, supporting the suggested ligand binding mode to La(III) in a chain structure, namely, every PhDC(2-) interacts with two La(III) cations through both carbonylic and both hydroxylic oxygens, and every La(III) cation binds four oxygen atoms of two different PhDC(2-).

Representation of Ion–Protein Interactions Using the Drude Polarizable Force-Field

PubMed Central

2016-01-01

Small metal ions play critical roles in numerous biological processes. Of particular interest is how metalloenzymes are allosterically regulated by the binding of specific ions. Understanding how ion binding affects these biological processes requires atomic models that accurately treat the microscopic interactions with the protein ligands. Theoretical approaches at different levels of sophistication can contribute to a deeper understanding of these systems, although computational models must strike a balance between accuracy and efficiency in order to enable long molecular dynamics simulations. In this study, we present a systematic effort to optimize the parameters of a polarizable force field based on classical Drude oscillators to accurately represent the interactions between ions (K+, Na+, Ca2+, and Cl–) and coordinating amino-acid residues for a set of 30 biologically important proteins. By combining ab initio calculations and experimental thermodynamic data, we derive a polarizable force field that is consistent with a wide range of properties, including the geometries and interaction energies of gas-phase ion/protein-like model compound clusters, and the experimental solvation free-energies of the cations in liquids. The resulting models display significant improvements relative to the fixed-atomic-charge additive CHARMM C36 force field, particularly in their ability to reproduce the many-body electrostatic nonadditivity effects estimated from ab initio calculations. The analysis clarifies the fundamental limitations of the pairwise additivity assumption inherent in classical fixed-charge force fields, and shows its dramatic failures in the case of Ca2+ binding sites. These optimized polarizable models, amenable to computationally efficient large-scale MD simulations, set a firm foundation and offer a powerful avenue to study the roles of the ions in soluble and membrane transport proteins. PMID:25578354

Conformational Contribution to Thermodynamics of Binding in Protein-Peptide Complexes through Microscopic Simulation

PubMed Central

Das, Amit; Chakrabarti, J.; Ghosh, Mahua

2013-01-01

We extract the thermodynamics of conformational changes in biomacromolecular complexes from the distributions of the dihedral angles of the macromolecules. These distributions are obtained from the equilibrium configurations generated via all-atom molecular dynamics simulations. The conformational thermodynamics data we obtained for calmodulin-peptide complexes using our methodology corroborate well with the experimentally observed conformational and binding entropies. The conformational free-energy changes and their contributions for different peptide-binding regions of calmodulin are evaluated microscopically. PMID:23528087

Neuraminidase inhibitor R-125489 - A promising drug for treating influenza virus: Steered molecular dynamics approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mai, Binh Khanh; Li, Mai Suan, E-mail: masli@ifpan.edu.pl

2011-07-08

Highlights: {yields} We study binding affinity of R-125489 and its prodrug CS-8958 to neuraminidase of pathogenic influenza viruses by molecular dynamics simulations. {yields} It is shown that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. {yields} We predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus. {yields} The high correlation between theoretical and experimental data implies that SMD is a very promising tool for drug design. -- Abstract: Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenzamore » virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson-Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design.« less

Quantum coherent tractor beam effect for atoms trapped near a nanowaveguide

PubMed Central

Sadgrove, Mark; Wimberger, Sandro; Nic Chormaic, Síle

2016-01-01

We propose several schemes to realize a tractor beam effect for ultracold atoms in the vicinity of a few-mode nanowaveguide. Atoms trapped near the waveguide are transported in a direction opposite to the guided mode propagation direction. We analyse three specific examples for ultracold 23Na atoms trapped near a specific nanowaveguide (i.e. an optical nanofibre): (i) a conveyor belt-type tractor beam effect, (ii) an accelerator tractor beam effect, and (iii) a quantum coherent tractor beam effect, all of which can effectively pull atoms along the nanofibre toward the light source. This technique provides a new tool for controlling the motion of particles near nanowaveguides with potential applications in the study of particle transport and binding as well as atom interferometry. PMID:27440516

Thermally stable single-atom platinum-on-ceria catalysts via atom trapping

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, John; Xiong, Haifeng; DelaRiva, Andrew

2016-07-08

Catalysts based on single atoms of scarce precious metals can lead to more efficient use through enhanced reactivity and selectivity. However, single atoms on catalyst supports can be mobile and aggregate into nanoparticles when heated at elevated temperatures. High temperatures are detrimental to catalyst performance unless these mobile atoms can be trapped. We used ceria powders having similar surface areas but different exposed surface facets. When mixed with a platinum/ aluminum oxide catalyst and aged in air at 800°C, the platinum transferred to the ceria and was trapped. Polyhedral ceria and nanorods were more effective than ceria cubes at anchoringmore » the platinum. Performing synthesis at high temperatures ensures that only the most stable binding sites are occupied, yielding a sinter-resistant, atomically dispersed catalyst.« less

Ab Initio Study of Aluminium Impurity and Interstitial-Substitutional Complexes in Ge Using a Hybrid Functional (HSE)

NASA Astrophysics Data System (ADS)

Igumbor, E.; Mapasha, R. E.; Meyer, W. E.

2017-07-01

The results of an ab initio modelling of aluminium substitutional impurity ({\\hbox {Al}}_Ge), aluminium interstitial in Ge [{\\hbox {I}}_Al for the tetrahedral (T) and hexagonal (H) configurations] and aluminium interstitial-substitutional pairs in Ge ({\\hbox {I}}_Al{\\hbox {Al}}_Ge) are presented. For all calculations, the hybrid functional of Heyd, Scuseria, and Ernzerhof in the framework of density functional theory was used. Defects formation energies, charge state transition levels and minimum energy configurations of the {\\hbox {Al}}_Ge, {\\hbox {I}}_Al and {\\hbox {I}}_Al{\\hbox {Al}}_Ge were obtained for -2, -1, 0, +1 and +2 charge states. The calculated formation energy shows that for the neutral charge state, the {\\hbox {I}}_Al is energetically more favourable in the T than the H configuration. The {\\hbox {I}}_Al{\\hbox {Al}}_Ge forms with formation energies of -2.37 eV and -2.32 eV, when the interstitial atom is at the T and H sites, respectively. The {\\hbox {I}}_Al{\\hbox {Al}}_Ge is energetically more favourable when the interstitial atom is at the T site with a binding energy of 0.8 eV. The {\\hbox {I}}_Al in the T configuration, induced a deep donor (+2/+1) level at EV+0.23 eV and the {\\hbox {Al}}_Ge induced a single acceptor level (0/-1) at EV+0.14 eV in the band gap of Ge. The {\\hbox {I}}_Al{\\hbox {Al}}_Ge induced double-donor levels are at E_V+0.06 and E_V+0.12 eV, when the interstitial atom is at the T and H sites, respectively. The {\\hbox {I}}_Al and {\\hbox {I}}_Al{\\hbox {Al}}_Ge exhibit properties of charge state-controlled metastability.

Unveiling the Atomic-Level Determinants of Acylase-Ligand Complexes: An Experimental and Computational Study.

PubMed

Mollica, Luca; Conti, Gianluca; Pollegioni, Loredano; Cavalli, Andrea; Rosini, Elena

2015-10-26

The industrial production of higher-generation semisynthetic cephalosporins starts from 7-aminocephalosporanic acid (7-ACA), which is obtained by deacylation of the naturally occurring antibiotic cephalosporin C (CephC). The enzymatic process in which CephC is directly converted into 7-ACA by a cephalosporin C acylase has attracted industrial interest because of the prospects of simplifying the process and reducing costs. We recently enhanced the catalytic efficiency on CephC of a glutaryl acylase from Pseudomonas N176 (named VAC) by a protein engineering approach and solved the crystal structures of wild-type VAC and the H57βS-H70βS VAC double variant. In the present work, experimental measurements on several CephC derivatives and six VAC variants were carried out, and the binding of ligands into the VAC active site was investigated at an atomistic level by means of molecular docking and molecular dynamics simulations and analyzed on the basis of the molecular geometry of encounter complex formation and protein-ligand potential of mean force profiles. The observed significant correlation between the experimental data and estimated binding energies highlights the predictive power of our computational method to identify the ligand binding mode. The present experimental-computational study is well-suited both to provide deep insight into the reaction mechanism of cephalosporin C acylase and to improve the efficiency of the corresponding industrial process.

Macroscopic modeling and simulations of supercoiled DNA with bound proteins

NASA Astrophysics Data System (ADS)

Huang, Jing; Schlick, Tamar

2002-11-01

General methods are presented for modeling and simulating DNA molecules with bound proteins on the macromolecular level. These new approaches are motivated by the need for accurate and affordable methods to simulate slow processes (on the millisecond time scale) in DNA/protein systems, such as the large-scale motions involved in the Hin-mediated inversion process. Our approaches, based on the wormlike chain model of long DNA molecules, introduce inhomogeneous potentials for DNA/protein complexes based on available atomic-level structures. Electrostatically, treat those DNA/protein complexes as sets of effective charges, optimized by our discrete surface charge optimization package, in which the charges are distributed on an excluded-volume surface that represents the macromolecular complex. We also introduce directional bending potentials as well as non-identical bead hydrodynamics algorithm to further mimic the inhomogeneous effects caused by protein binding. These models thus account for basic elements of protein binding effects on DNA local structure but remain computational tractable. To validate these models and methods, we reproduce various properties measured by both Monte Carlo methods and experiments. We then apply the developed models to study the Hin-mediated inversion system in long DNA. By simulating supercoiled, circular DNA with or without bound proteins, we observe significant effects of protein binding on global conformations and long-time dynamics of the DNA on the kilo basepair length.

Energy spectra of small bosonic clusters having a large two-body scattering length

NASA Astrophysics Data System (ADS)

Gattobigio, M.; Kievsky, A.; Viviani, M.

2012-10-01

In this work we investigate small clusters of bosons using the hyperspherical harmonic basis. We consider systems with A=2,3,4,5,6 particles interacting through a soft interparticle potential. In order to make contact with a real system, we use an attractive Gaussian potential that reproduces the values of the dimer binding energy and the atom-atom scattering length obtained with one of the most widely used 4He-4He interactions, the LM2M2 potential of Aziz and Slaman. The intensity of the potential is varied in order to explore the clusters’ spectra in different regions with large positive and large negative values of the two-body scattering length. In addition, we include a repulsive three-body force to reproduce the trimer binding energy. With this model, consisting in the sum of a two- and three-body potential, we have calculated the spectrum of the four-, five-, and six-particle systems. In all the regions explored, we have found that these systems present two states, one deep and one shallow close to the A-1 threshold. Some universal relations between the energy levels are extracted; in particular, we have estimated the universal ratios between thresholds of the three-, four-, and five-particle continua using the two-body Gaussian potential. They agree with recent measurements and theoretical predictions.

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance.

PubMed

Marques, M Paula M; Gianolio, Diego; Cibin, Giannantonio; Tomkinson, John; Parker, Stewart F; Valero, Rosendo; Pedro Lopes, R; Batista de Carvalho, Luis A E

2015-02-21

The interaction of the widely used anticancer drug cisplatin with DNA bases was studied by EXAFS and vibrational spectroscopy (FTIR, Raman and INS), coupled with DFT/plane-wave calculations. Detailed information was obtained on the local atomic structure around the Pt(ii) centre, both in the cisplatin-purine (adenine and guanine) and cisplatin-glutathione adducts. Simultaneous neutron and Raman scattering experiments allowed us to obtain a reliable and definite picture of this cisplatin interplay with its main pharmacological target (DNA), at the molecular level. The vibrational experimental spectra were fully assigned in the light of the calculated pattern for the most favoured geometry of each drug-purine adduct, and cisplatin's preference for guanine (G) relative to adenine (A) within the DNA double helix was experimentally verified: a complete N by S substitution in the metal coordination sphere was only observed for [cDDP-A2], reflecting a somewhat weaker Pt-A binding relative to Pt-G. The role of glutathione on the drug's pharmacokinetics, as well as on the stability of platinated DNA adducts, was evaluated as this is the basis for glutathione-mediated intracellular drug scavenging and in vivo resistance to Pt-based anticancer drugs. Spectroscopic evidence of the metal's preference for glutathione's sulfur over purine's nitrogen binding sites was gathered, at least two sulfur atoms being detected in platinum's first coordination sphere.

Reactions of mixed silver-gold cluster cations AgmAun+ (m+n=4,5,6) with CO: Radiative association kinetics and density functional theory computations

NASA Astrophysics Data System (ADS)

Neumaier, Marco; Weigend, Florian; Hampe, Oliver; Kappes, Manfred M.

2006-09-01

Near thermal energy reactive collisions of small mixed metal cluster cations AgmAun+ (m +n=4, 5, and 6) with carbon monoxide have been studied in the room temperature Penning trap of a Fourier transform ion-cyclotron-resonance mass spectrometer as a function of cluster size and composition. The tetrameric species AgAu3+ and Ag2Au2+ are found to react dissociatively by way of Au or Ag atom loss, respectively, to form the cluster carbonyl AgAu2CO+. In contrast, measurements on a selection of pentamers and hexamers show that CO is added with absolute rate constants that decrease with increasing silver content. Experimentally determined absolute rate constants for CO adsorption were analyzed using the radiative association kinetics model to obtain cluster cation-CO binding energies ranging from 0.77to1.09eV. High-level ab initio density functional theory (DFT) computations identifying the lowest-energy cluster isomers and the respective CO adsorption energies are in good agreement with the experimental findings clearly showing that CO binds in a "head-on" fashion to a gold atom in the mixed clusters. DFT exploration of reaction pathways in the case of Ag2Au2+ suggests that exoergicities are high enough to access the minimum energy products for all reactive clusters probed.

Surface passivation for tight-binding calculations of covalent solids.

PubMed

Bernstein, N

2007-07-04

Simulation of a cluster representing a finite portion of a larger covalently bonded system requires the passivation of the cluster surface. We compute the effects of an explicit hybrid orbital passivation (EHOP) on the atomic structure in a model bulk, three-dimensional, narrow gap semiconductor, which is very different from the wide gap, quasi-one-dimensional organic molecules where most passivation schemes have been studied in detail. The EHOP approach is directly applicable to minimal atomic orbital basis methods such as tight-binding. Each broken bond is passivated by a hybrid created from an explicitly expressed linear combination of basis orbitals, chosen to represent the contribution of the missing neighbour, e.g. a sp(3) hybrid for a single bond. The method is tested by computing the forces on atoms near a point defect as a function of cluster geometry. We show that, compared to alternatives such as pseudo-hydrogen passivation, the force on an atom converges to the correct bulk limit more quickly as a function of cluster radius, and that the force is more stable with respect to perturbations in the position of the cluster centre. The EHOP method also obviates the need for parameterizing the interactions between the system atoms and the passivating atoms. The method is useful for cluster calculations of non-periodic defects in large systems and for hybrid schemes that simulate large systems by treating finite regions with a quantum-mechanical model, coupled to an interatomic potential description of the rest of the system.

Surface passivation for tight-binding calculations of covalent solids

NASA Astrophysics Data System (ADS)

Bernstein, N.

2007-07-01

Simulation of a cluster representing a finite portion of a larger covalently bonded system requires the passivation of the cluster surface. We compute the effects of an explicit hybrid orbital passivation (EHOP) on the atomic structure in a model bulk, three-dimensional, narrow gap semiconductor, which is very different from the wide gap, quasi-one-dimensional organic molecules where most passivation schemes have been studied in detail. The EHOP approach is directly applicable to minimal atomic orbital basis methods such as tight-binding. Each broken bond is passivated by a hybrid created from an explicitly expressed linear combination of basis orbitals, chosen to represent the contribution of the missing neighbour, e.g. a sp3 hybrid for a single bond. The method is tested by computing the forces on atoms near a point defect as a function of cluster geometry. We show that, compared to alternatives such as pseudo-hydrogen passivation, the force on an atom converges to the correct bulk limit more quickly as a function of cluster radius, and that the force is more stable with respect to perturbations in the position of the cluster centre. The EHOP method also obviates the need for parameterizing the interactions between the system atoms and the passivating atoms. The method is useful for cluster calculations of non-periodic defects in large systems and for hybrid schemes that simulate large systems by treating finite regions with a quantum-mechanical model, coupled to an interatomic potential description of the rest of the system.

First Principles Predictions of the Structure and Function of G-Protein-Coupled Receptors: Validation for Bovine Rhodopsin

PubMed Central

Trabanino, Rene J.; Hall, Spencer E.; Vaidehi, Nagarajan; Floriano, Wely B.; Kam, Victor W. T.; Goddard, William A.

2004-01-01

G-protein-coupled receptors (GPCRs) are involved in cell communication processes and with mediating such senses as vision, smell, taste, and pain. They constitute a prominent superfamily of drug targets, but an atomic-level structure is available for only one GPCR, bovine rhodopsin, making it difficult to use structure-based methods to design receptor-specific drugs. We have developed the MembStruk first principles computational method for predicting the three-dimensional structure of GPCRs. In this article we validate the MembStruk procedure by comparing its predictions with the high-resolution crystal structure of bovine rhodopsin. The crystal structure of bovine rhodopsin has the second extracellular (EC-II) loop closed over the transmembrane regions by making a disulfide linkage between Cys-110 and Cys-187, but we speculate that opening this loop may play a role in the activation process of the receptor through the cysteine linkage with helix 3. Consequently we predicted two structures for bovine rhodopsin from the primary sequence (with no input from the crystal structure)—one with the EC-II loop closed as in the crystal structure, and the other with the EC-II loop open. The MembStruk-predicted structure of bovine rhodopsin with the closed EC-II loop deviates from the crystal by 2.84 Å coordinate root mean-square (CRMS) in the transmembrane region main-chain atoms. The predicted three-dimensional structures for other GPCRs can be validated only by predicting binding sites and energies for various ligands. For such predictions we developed the HierDock first principles computational method. We validate HierDock by predicting the binding site of 11-cis-retinal in the crystal structure of bovine rhodopsin. Scanning the whole protein without using any prior knowledge of the binding site, we find that the best scoring conformation in rhodopsin is 1.1 Å CRMS from the crystal structure for the ligand atoms. This predicted conformation has the carbonyl O only 2.82 Å from the N of Lys-296. Making this Schiff base bond and minimizing leads to a final conformation only 0.62 Å CRMS from the crystal structure. We also used HierDock to predict the binding site of 11-cis-retinal in the MembStruk-predicted structure of bovine rhodopsin (closed loop). Scanning the whole protein structure leads to a structure in which the carbonyl O is only 2.85 Å from the N of Lys-296. Making this Schiff base bond and minimizing leads to a final conformation only 2.92 Å CRMS from the crystal structure. The good agreement of the ab initio-predicted protein structures and ligand binding site with experiment validates the use of the MembStruk and HierDock first principles' methods. Since these methods are generic and applicable to any GPCR, they should be useful in predicting the structures of other GPCRs and the binding site of ligands to these proteins. PMID:15041637

Doping Scheme in Atomic Chain Electronics

NASA Technical Reports Server (NTRS)

Toshishige, Yamada

1997-01-01

Due to the dramatic reduction in MOS size, there appear many unwanted effects. In these small devices, the number of dopant atoms in the channel is not macroscopic and electrons may suffer significantly different scattering from device to device since the spatial distribution of dopant atoms is no longer regarded as continuous. This prohibits integration, while it is impossible to control such dopant positions within atomic scale. A fundamental solution is to create electronics with simple but atomically precise structures, which could be fabricated with recent atom manipulation technology. All the constituent atoms are placed as planned, and then the device characteristics are deviation-free, which is mandatory for integration. Atomic chain electronics belongs to this category. Foreign atom chains or arrays form devices, and they are placed on the atomically flat substrate surface. We can design the band structure and the resultant Fermi energy of these structures by manipulating the lattice constant. Using the tight-binding theory with universal parameters, it has been predicted that isolated Si chains and arrays are metallic, Mg chains are insulating, and Mg arrays have metallic and insulating phases [1]. The transport properties along a metallic chain have been studied, emphasizing the role of the contact to electrodes [2]. For electronic applications, it is essential to establish a method to dope a semiconducting chain, which is to control the Fermi energy position without altering the original band structure. If we replace some of the chain atoms with dopant atoms randomly, the electrons will see random potential along die chain and will be localized strongly in space (Anderson localization). However, if we replace periodically, although the electrons can spread over the chain, there will generally appear new bands and band gaps reflecting the new periodicity of dopant atoms. This will change the original band structure significantly. In order to overcome this dilemma, we may place a dopant atom beside the chain at every N lattice periods (N > 1). Because of the periodic arrangement of pant atoms, we can avoid the unwanted Anderson localization. Moreover, since the dopant atoms do not constitute the chain, the overlap interaction between them is minimized, and the band structure modification can be made smallest. Some tight-binding results will be discussed to demonstrate the present idea.

Deep analysis of N-cadherin/ADH-1 interaction: a computational survey.

PubMed

Eslami, Mahboobeh; Nezafat, Navid; Khajeh, Sahar; Mostafavi-Pour, Zohreh; Bagheri Novir, Samaneh; Negahdaripour, Manica; Ghasemi, Younes; Razban, Vahid

2018-01-19

Due to the considerable role of N-cadherin in cancer metastasis, tumor growth, and progression, inhibition of this protein has been highly regarded in recent years. Although ADH-1 has been known as an appropriate inhibitor of N-cadherin in clinical trials, its chemical nature and binding mode with N-cadherin have not been precisely specified yet. Accordingly, in this study, quantum mechanics calculations were used to investigate the chemical nature of ADH-1. These calculations clarify the molecular properties of ADH-1 and determine its reactive sites. Based on the results, the oxygen atoms are suitable for electrophilic reactivity, while the hydrogen atoms that are connected to nitrogen atoms are the favorite sites for nucleophilic reactivity. The higher electronegativity of the oxygen atoms makes them the most reactive portions in this molecule. Molecular docking and molecular dynamics (MD) simulation have also been applied to specify the binding mode of ADH-1 with N-cadherin and determine the important residues of N-cadherin involving in the interaction with ADH-1. Moreover, the verified model by MD simulation has been studied to extract the free energy value and find driving forces. These calculations and molecular electrostatic potential map of ADH-1 indicated that hydrophobic and electrostatic interactions are almost equally involved in the implantation of ADH-1 in the N-cadherin binding site. The presented results not only enable a closer examination of N-cadherin in complex with ADH-1 molecule, but also are very beneficial in designing new inhibitors for N-cadherin and can help to save time and cost in this field.

Modeling linear and cyclic PKS intermediates through atom replacement.

PubMed

Shakya, Gaurav; Rivera, Heriberto; Lee, D John; Jaremko, Matt J; La Clair, James J; Fox, Daniel T; Haushalter, Robert W; Schaub, Andrew J; Bruegger, Joel; Barajas, Jesus F; White, Alexander R; Kaur, Parminder; Gwozdziowski, Emily R; Wong, Fiona; Tsai, Shiou-Chuan; Burkart, Michael D

2014-12-03

The mechanistic details of many polyketide synthases (PKSs) remain elusive due to the instability of transient intermediates that are not accessible via conventional methods. Here we report an atom replacement strategy that enables the rapid preparation of polyketone surrogates by selective atom replacement, thereby providing key substrate mimetics for detailed mechanistic evaluations. Polyketone mimetics are positioned on the actinorhodin acyl carrier protein (actACP) to probe the underpinnings of substrate association upon nascent chain elongation and processivity. Protein NMR is used to visualize substrate interaction with the actACP, where a tetraketide substrate is shown not to bind within the protein, while heptaketide and octaketide substrates show strong association between helix II and IV. To examine the later cyclization stages, we extended this strategy to prepare stabilized cyclic intermediates and evaluate their binding by the actACP. Elongated monocyclic mimics show much longer residence time within actACP than shortened analogs. Taken together, these observations suggest ACP-substrate association occurs both before and after ketoreductase action upon the fully elongated polyketone, indicating a key role played by the ACP within PKS timing and processivity. These atom replacement mimetics offer new tools to study protein and substrate interactions and are applicable to a wide variety of PKSs.

2D polymeric cadmium(II) complexes containing 1,3-imidazolidine-2-thione (Imt) ligand, [Cd(Imt)(H2O)2(SO4)]n and [Cd(Imt)2(N3)2]n

NASA Astrophysics Data System (ADS)

Mahmood, Rashid; Ahmad, Saeed; Fettouhi, Mohammed; Roisnel, Thierry; Gilani, Mazhar Amjad; Mehmood, Kashif; Murtaza, Ghulam; Isab, Anvarhusein A.

2018-03-01

The present study aims at preparing and carrying out the structural investigation of two polymeric cadmium(II) complexes of imidazolidine-2-thione (Imt) based on sulfate or azide ions, [Cd(Imt)(H2O)2(SO4)]n (1) and [Cd(Imt)2(N3)2]n (2). The structures of the complexes were determined by single crystal X-ray analysis. Both compounds, 1 and 2 crystallize in the form of 2D coordination polymers and the cadmium(II) ion is six-coordinate having a distorted octahedral geometry in each compound. In 1, the metal ion is bonded to one sulfur atom of Imt and five oxygen atoms with two from water and three of bridging sulfate ions. In 2, the cadmium coordination sphere is completed by two Imt molecules binding through the sulfur atoms and four nitrogen atoms of bridging azide ions. The crystal structures are stabilized by intra and intermolecular hydrogen bonding interactions. The complexes were also characterized by IR and NMR spectroscopy and the spectroscopic data is consistent with the binding of the ligands.

A Novel, Highly Stable Fold of the Immunoglobulin Binding Domain of Streptococcal Protein G

NASA Astrophysics Data System (ADS)

Gronenborn, Angela M.; Filpula, David R.; Essig, Nina Z.; Achari, Aniruddha; Whitlow, Marc; Wingfield, Paul T.; Marius Clore, G.

1991-08-01

The high-resolution three-dimensional structure of a single immunoglobulin binding domain (B1, which comprises 56 residues including the NH_2-terminal Met) of protein G from group G Streptococcus has been determined in solution by nuclear magnetic resonance spectroscopy on the basis of 1058 experimental restraints. The average atomic root-mean-square distribution about the mean coordinate positions is 0.27 angstrom (overset{circ}{mathrm A}) for the backbone atoms, 0.65 overset{circ}{mathrm A} for all atoms, and 0.39 overset{circ}{mathrm A} for atoms excluding disordered surface side chains. The structure has no disulfide bridges and is composed of a four-stranded β sheet, on top of which lies a long helix. The central two strands (β 1 and β 4), comprising the NH_2- and COOH-termini, are parallel, and the outer two strands (β 2 and β 3) are connected by the helix in a +3x crossover. This novel topology (-1, +3x, -1), coupled with an extensive hydrogen-bonding network and a tightly packed and buried hydrophobic core, is probably responsible for the extreme thermal stability of this small domain (reversible melting at 87^circC).

De-Excitation of High-Rydberg Antihydrogen in a Strongly Magnetized Pure Positron Plasma

NASA Astrophysics Data System (ADS)

Bass, E. M.

2005-10-01

The rate at which highly excited atoms relax to deeper binding is found with classical theories and simulations. This rate relates to antihydrogen formation experiments where such atoms are formed in pure-positron, Penning trap plasmas.ootnotetextG.Gabrielse, N.S. Bowden, P. Oxley, et al., Phys. Rev. Lett. 89, 213401 (2002); M. Amoretti, C. Amsler, G. Bonomi, et al., Nature (London) 419, 456 (2002). The analysis concerns atoms that have passed the kinetic bottleneck at binding energy ɛ 4kT.ootnotetextM.E. Glinsky and T.M. O'Neil, Phys. Fluids B 3, 1279 (1991). Energy loss caused by collisions between atoms and plasma positrons is calculated in two ways: For close collisions, a molecular dynamics simulation gives the energy loss; for large-impact parameter collisions, theoretical expressions based on Fokker-Planck theory are employed.ootnotetextEric M. Bass and Daniel H.E. Dubin, Phys. Plasmas 11, 1240 (2004). For a finite magnetic field, the energy loss rate scales as 1/ɛ, just as for infinite field,^2 but with a larger coefficient. A statistical description of energy loss by radiation and Stark mixing will also be discussed.

Reaction of hydrogen with Ag(111): binding states, minimum energy paths, and kinetics.

PubMed

Montoya, Alejandro; Schlunke, Anna; Haynes, Brian S

2006-08-31

The interaction of atomic and molecular hydrogen with the Ag(111) surface is studied using periodic density functional total-energy calculations. This paper focuses on the site preference for adsorption, ordered structures, and energy barriers for H diffusion and H recombination. Chemisorbed H atoms are unstable with respect to the H(2) molecule in all adsorption sites below monolayer coverage. The three-hollow sites are energetically the most favorable for H chemisorption. The binding energy of H to the surface decreases slightly up to one monolayer, suggesting a small repulsive H-H interaction on nonadjacent sites. Subsurface and vacancy sites are energetically less favorable for H adsorption than on-top sites. Recombination of chemisorbed H atoms leads to the formation of gas-phase H(2) with no molecular chemisorbed state. Recombination is an exothermic process and occurs on the bridge site with a pronounced energy barrier. This energy barrier is significantly higher than that inferred from experimental temperature-programmed desorption (TPD) studies. However, there is significant permeability of H atoms through the recombination energy barrier at low temperatures, thus increasing the rate constant for H(2) desorption due to quantum tunneling effects, and improving the agreement between experiment and theory.

Binding effects of Mn²⁺ and Zn²⁺ ions on the vibrational properties of guanine-cytosine base pairs in the Watson-Crick and Hoogsteen configurations.

PubMed

Morari, Cristian; Bogdan, Diana; Muntean, Cristina M

2012-11-01

The binding effects of Mn²⁺ and Zn²⁺ ions on the vibrational properties of guanine-cytosine base pairs have been performed using density functional theory investigations. The calculations were carried out on Watson-Crick and Hoogsteen configurations of the base pairs. We have found, that in Watson-Crick configuration, the metal is coordinated to N7 atom of guanine while, in the case of Hoogsteen configuration, the coordination is at N3 atom of guanine. We have pointed out the vibrational bands that can be used to detect the presence of metallic ions in the Watson-Crick and Hoogsteen structures. Our results show that the vibrational amplitudes of metallic atoms are strong for wavenumbers lower than 600 cm⁻¹. Also, we predict that the distinction between Watson-Crick and Hoogsteen configurations can be seen around 85, 170 and 310 cm⁻¹.

Tackling CO Poisoning with Single Atom Alloy Catalysts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Jilei; Lucci, Felicia R.; Yang, Ming

2016-05-01

Platinum (Pt) catalysts are extensively used in the chemical industry and as electrocatalysts in fuel cells. Pt is notorious for its sensitivity to poisoning by strong CO adsorption. Here we demonstrate that the single atom alloy (SAA) strat-egy applied to Pt reduces the binding strength of CO while maintaining catalytic performance. By using surface sensi-tive studies, we accurately determined the binding strength of CO to different Pt ensembles, and this in turn guided the preparation of PtCu alloy nanoparticles. The atomic ratio Pt:Cu = 1:120 yielded a SAA which exhibited excellent CO tolerance in H2 activation, the key elementary stepmore » for hy-drogenation and hydrogen electro-oxidation. As a probe reaction, the selective hydrogenation of acetylene to ethene was performed under flow conditions on the SAA nanopar-ticles supported on alumina without activity loss in the pres-ence of CO. The ability to maintain reactivity in the presence of CO is vital to other industrial reactions including fuel reforming and methanol/ethanol fuel cells.« less

DFT STUDY OF HYDROGEN STORAGE ON Li- AND Na-DOPED C59B HETEROFULLERENE

NASA Astrophysics Data System (ADS)

Zahedi, Ehsan; Mozaffari, Majid

2014-05-01

Effect of light alkali metal (Li and Na) decorated on the C59B heterofullerene for hydrogen storage is considered using DFT-MPW1PW91 method. Results show that Li and Na atoms strongly prefer to adsorb on top of five-member and six-member ring where a carbon atom is replaced by a boron atom. Significant charge transfer from the alkali metal to the C59B compensates for the electron deficiency of C59B and makes the latter aromatic in nature. Corrected binding energies of hydrogen molecule on the alkali-doped C59B using counterpoise method, structural properties and NBO analysis indicate that first hydrogen molecule is adsorbed physically and does not support minimal conditions of DOE requirement. Finally, positive values of binding energies for the adsorption of a second hydrogen molecule show that alkali doped C59B are capable of storing a maximum of one hydrogen molecule.

Mechanical coupling in myosin V: a simulation study

PubMed Central

Ovchinnikov, Victor; Trout, Bernhardt L.

2009-01-01

Myosin motor function depends on the interaction between different domains that transmit information from one part of the molecule to another. The inter-domain coupling in myosin V is studied with Restrained Targeted Molecular Dynamics (RTMD) using an all-atom representation in explicit solvent. To elucidate the origin of the conformational change due to the binding of ATP, targeting forces are applied to small sets of atoms (the forcing sets, FS) in the direction of their displacement from the rigor conformation, which has a closed actin-binding cleft, to the post-rigor conformation, in which the cleft is open. The ‘minimal’ FS that results in extensive structural changes in the overall myosin conformation is comprised of the ATP, Switch 1, and the nearby HF, HG and HH helices. Addition of switch 2 to the forcing set is required to achieve a complete opening of the actin-binding cleft. The RTMD simulations reveal the mechanical coupling pathways between (i) the nucleotide-binding pocket (NBP) and the actin-binding cleft, (ii) the NBP and the converter, and (iii) the actin-binding cleft and the converter. Closing of the NBP due to ATP binding is tightly coupled to the opening of the cleft, and leads to the rupture of a key hydrogen bond (F441N/A684O) between switch 2 and the SH1 helix. The actin-binding cleft may mediate the rupture of this bond via a connection between the HW helix, the Relay helix, and Switch 2. The findings are consistent with experimental studies and a recent normal mode analysis. The present method is expected to be useful more generally in studies of inter-domain coupling in proteins. PMID:19853615

Mechanical coupling in myosin V: a simulation study.

PubMed

Ovchinnikov, Victor; Trout, Bernhardt L; Karplus, Martin

2010-01-29

Myosin motor function depends on the interaction between different domains that transmit information from one part of the molecule to another. The interdomain coupling in myosin V is studied with restrained targeted molecular dynamics using an all-atom representation in explicit solvent. To elucidate the origin of the conformational change due to the binding of ATP, targeting forces are applied to small sets of atoms (the forcing sets, FSs) in the direction of their displacement from the rigor conformation, which has a closed actin-binding cleft, to the post-rigor conformation, in which the cleft is open. The "minimal" FS that results in extensive structural changes in the overall myosin conformation is composed of ATP, switch 1, and the nearby HF, HG, and HH helices. Addition of switch 2 to the FS is required to achieve a complete opening of the actin-binding cleft. The restrained targeted molecular dynamics simulations reveal the mechanical coupling pathways between (i) the nucleotide-binding pocket (NBP) and the actin-binding cleft, (ii) the NBP and the converter, and (iii) the actin-binding cleft and the converter. Closing of the NBP due to ATP binding is tightly coupled to the opening of the cleft and leads to the rupture of a key hydrogen bond (F441N/A684O) between switch 2 and the SH1 helix. The actin-binding cleft may mediate the rupture of this bond via a connection between the HW helix, the relay helix, and switch 2. The findings are consistent with experimental studies and a recent normal mode analysis. The present method is expected to be useful more generally in studies of interdomain coupling in proteins.

Molecular modeling and multispectroscopic studies of the interaction of mesalamine with bovine serum albumin.

PubMed

Shahabadi, Nahid; Fili, Soraya Moradi

2014-01-24

The interaction of mesalamine (5-aminosalicylic acid (5-ASA)) with bovine serum albumin (BSA) was investigated by fluorescence quenching, absorption spectroscopy, circular dichroism (CD) techniques, and molecular docking. Thermodynamic parameters (ΔH<0 and ΔS 0) indicated that the hydrogen bond and electrostatic forces played the major role in the binding of 5-ASA to BSA. The results of CD and UV-vis spectroscopy showed that the binding of this drug to BSA induces some conformational changes in BSA. Displacement experiments predicted that the binding of 5-ASA to BSA is located within domain III, Sudlows site 2, that these observations were substantiated by molecular docking studies. In addition, the docking result shows that the 5-ASA in its anionic form mainly interacts with Gln-416 residue through one hydrogen bond between H atom of 5-ASA anion and the adjacent O atom of the hydroxyl group of Gln-416. Copyright © 2013 Elsevier B.V. All rights reserved.

Robust, self-assembled, biocompatible films

DOEpatents

Swanson, Basil I; Anderson, Aaron S.; Dattelbaum, Andrew M.; Schmidt, Jurgen G.

2014-06-24

The present invention provides a composite material including a substrate having an oxide surface, and, a continuous monolayer on the oxide surface, the monolayer including a silicon atom from a trifunctional alkyl/alkenyl/alkynyl silane group that attaches to the oxide surface, an alkyl/alkenyl/alkynyl portion of at least three carbon atoms, a polyalkylene glycol spacer group, and either a reactive site (e.g., a recognition ligand) or a site resistant to non-specific binding (e.g., a methoxy or the like) at the terminus of each modified SAM. The present invention further provides a sensor element, a sensor array and a method of sensing, each employing the composite material. Patterning is also provided together with backfilling to minimize non-specific binding.

Superhalogens as building blocks of two-dimensional organic-inorganic hybrid perovskites for optoelectronics applications.

PubMed

Yao, Qiushi; Fang, Hong; Deng, Kaiming; Kan, Erjun; Jena, Puru

2016-10-20

Organic-inorganic hybrid perovskites, well known for their potential as the next generation solar cells, have found another niche application in optoelectronics. This was demonstrated in a recent experiment (L. Dou, et al., Science, 2015, 349, 1518) on atomically thin (C 4 H 9 NH 3 ) 2 PbBr 4 , where, due to quantum confinement, the bandgap and the exciton binding energy are enhanced over their corresponding values in the three-dimensional bulk phase. Using density functional theory we show that when halogen atoms (e.g. I) are sequentially replaced with superhalogen molecules (e.g. BH 4 ) the bandgap and exciton binding energy increase monotonically with the superhalogen content with the exciton binding energy of (C 4 H 9 NH 3 ) 2 Pb(BH 4 ) 4 approaching the value in monolayer black phosphorus. Lead-free admixtures (C 4 H 9 NH 3 ) 2 MI 4-x (BH 4 ) x (M = Sn and Ge; x = 0-4) also show a similar trend. Thus, a combination of quantum confinement and compositional change can be used as an effective strategy to tailor the bandgap and the exciton binding energy of two-dimensional hybrid perovskites, making them promising candidates for optoelectronic applications.

Assembly of streptolysin O pores assessed by quartz crystal microbalance and atomic force microscopy provides evidence for the formation of anchored but incomplete oligomers.

PubMed

Stewart, Sarah E; D'Angelo, Michael E; Paintavigna, Stefania; Tabor, Rico F; Martin, Lisandra L; Bird, Phillip I

2015-01-01

Streptolysin O (SLO) is a bacterial pore forming protein that is part of the cholesterol dependent cytolysin (CDC) family. We have used quartz crystal microbalance with dissipation monitoring (QCM-D) to examine SLO membrane binding and pore formation. In this system, SLO binds tightly to cholesterol-containing membranes, and assembles into partial and complete pores confirmed by atomic force microscopy. SLO binds to the lipid bilayer at a single rate consistent with the Langmuir isotherm model of adsorption. Changes in dissipation illustrate that SLO alters the viscoelastic properties of the bilayer during pore formation, but there is no loss of material from the bilayer as reported for small membrane-penetrating peptides. SLO mutants were used to further dissect the assembly and insertion processes by QCM-D. This shows the signature of SLO in QCM-D changes when pore formation is inhibited, and that bound and inserted SLO forms can be distinguished. Furthermore a pre-pore locked SLO mutant binds reversibly to lipid, suggesting that the partially complete wtSLO forms observed by AFM are anchored to the membrane. Copyright © 2014 Elsevier B.V. All rights reserved.

Structural, electronic and magnetic properties of Ti n Mo ( n = 1 - 7) clusters

NASA Astrophysics Data System (ADS)

Zhang, Ge; Zhai, Zhongyuan; Sheng, Yong

2017-04-01

The ground state structures of TinMo and Tin+1 (n = 1 - 7) clusters and their structural, electronic and magnetic properties are investigated with the density functional method at B3LYP/LanL2DZ level. One Mo atom substituted Tin+1 structure is the dominant growth pattern, and the TinMo clusters exhibit enhanced structural stabilities according to the averaged binding energies. The electronic properties are also discussed by investigating chemical hardness and HOMO-LUMO energy gap. The results reveal that Ti3Mo and Ti5Mo keep higher chemical stabilities when compared with the other clusters. For all the studied clusters, the Mo atoms always get electrons from Ti atoms and present negative charges. Moreover, the doping of Mo in the bare titanium clusters can alter the magnetic moments of them. Ti3Mo and Ti5Mo show relatively large total magnetic moments, which may be related to the presence of exchange splitting behavior in their densities of states. Supplementary material in the form of one pdf file available from the Journal web page at http://https://doi.org/10.1140/epjd/e2017-70589-8

Tight-binding molecular-dynamics study of point defects in GaAs

NASA Astrophysics Data System (ADS)

Seong, Hyangsuk; Lewis, Laurent J.

1995-08-01

Tight-binding molecular-dynamics simulations at 0 K have been performed in order to study the effect of defects (vacancies and antisites) in different states of charge on the electronic and structural properties of GaAs. Relaxations are fully included in the model, and for each defect we calculate the local atomic structure, the volume change upon relaxing, the formation energy (including chemical potential contributions), and the ionization levels. We find Ga vacancies to relax by an amount which is independent of the state of charge, consistent with positron lifetime measurements. Our calculations also predict Ga vacancies to exhibit a negative-U effect, and to assume a triply negative charge state for most values of the electron chemical potential. The relaxation of As vacancies, on the contrary, depends sensitively on the state of charge. The model confirms the two experimentally observed ionization levels for this defect, just below the conduction-band minimum. Likewise, Ga antisites exhibit large relaxations. In fact, in the neutral state, relaxation is so large that it leads to a ``broken-bond'' configuration, in excellent accord with the first-principles calculations of Zhang and Chadi [Phys. Rev. Lett. 64, 1789 (1990)]. This system also exhibits a negative-U effect, for values of the electron chemical potential near midgap. For As antisites, we find only a weak relaxation, independent of the charge. The model predicts the neutral state of the defect to be the ground state for values of the electron chemical potential near and above midgap, which supports the view that the EL2 defect is a neutral As antisite. Upon comparing the formation energies of the various defects we finally find that, for all values of the atomic chemical potentials, antisites are most likely to occur than vacancies.

The allosteric switching mechanism in bacteriophage MS2

NASA Astrophysics Data System (ADS)

Perkett, Matthew R.; Mirijanian, Dina T.; Hagan, Michael F.

2016-07-01

We use all-atom simulations to elucidate the mechanisms underlying conformational switching and allostery within the coat protein of the bacteriophage MS2. Assembly of most icosahedral virus capsids requires that the capsid protein adopts different conformations at precise locations within the capsid. It has been shown that a 19 nucleotide stem loop (TR) from the MS2 genome acts as an allosteric effector, guiding conformational switching of the coat protein during capsid assembly. Since the principal conformational changes occur far from the TR binding site, it is important to understand the molecular mechanism underlying this allosteric communication. To this end, we use all-atom simulations with explicit water combined with a path sampling technique to sample the MS2 coat protein conformational transition, in the presence and absence of TR-binding. The calculations find that TR binding strongly alters the transition free energy profile, leading to a switch in the favored conformation. We discuss changes in molecular interactions responsible for this shift. We then identify networks of amino acids with correlated motions to reveal the mechanism by which effects of TR binding span the protein. We find that TR binding strongly affects residues located at the 5-fold and quasi-sixfold interfaces in the assembled capsid, suggesting a mechanism by which the TR binding could direct formation of the native capsid geometry. The analysis predicts amino acids whose substitution by mutagenesis could alter populations of the conformational substates or their transition rates.

A comparative study for Hydrogen storage in metal decorated graphyne nanotubes and graphyne monolayers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Jinlian; Guo, Yanhua; Zhang, Yun

A comparative study for hydrogen storage in metal decorated graphyne nanotubes and graphyne monolayers has been investigated within the framework of first-principle calculations. Our results show that the binding energies of Li, Ca, Sc, Ti on graphyne nanotubes are stronger than that on graphyne monolayers. Such strong binding would prevent the formation of metal clusters on graphyne nanotubes. From the charge transfer and partial density of states, it is found that the curvature effect of nanotubes plays an important role for the strong binding strength of metal on graphyne nanotubes. And the hydrogen storage capacity is 4.82 wt%, 5.08 wt%,more » 4.88 wt%, 4.76 wt% for Li, Ca, Sc, Ti decorated graphyne nanotubes that promise a potential material for storing hydrogen. - Graphical abstract: Metal atoms (Li, Ca, Sc and Ti) can strongly bind to graphyne nanotubes to avoid the formation of metal clusters, and a capacity of Ca@graphyne nanotube is 5.08 wt% which is close to the requirement of DOE in 2015. Twenty-four hydrogen molecules absorb to Ti-decorated graphyne nanotube. - Highlights: • The binding strength for metal on graphyne nanotubes is much stronger than that on γ-graphyne monolayer. • Metal atoms can strongly bind to the curving triangle acetylenes rings to avoid the formation of metal clusters. • A capacity of Ca@graphyne nanotube is 5.08 wt% which is close to the requirement of DOE in 2015.« less

Computational design of enzyme-ligand binding using a combined energy function and deterministic sequence optimization algorithm.

PubMed

Tian, Ye; Huang, Xiaoqiang; Zhu, Yushan

2015-08-01

Enzyme amino-acid sequences at ligand-binding interfaces are evolutionarily optimized for reactions, and the natural conformation of an enzyme-ligand complex must have a low free energy relative to alternative conformations in native-like or non-native sequences. Based on this assumption, a combined energy function was developed for enzyme design and then evaluated by recapitulating native enzyme sequences at ligand-binding interfaces for 10 enzyme-ligand complexes. In this energy function, the electrostatic interaction between polar or charged atoms at buried interfaces is described by an explicitly orientation-dependent hydrogen-bonding potential and a pairwise-decomposable generalized Born model based on the general side chain in the protein design framework. The energy function is augmented with a pairwise surface-area based hydrophobic contribution for nonpolar atom burial. Using this function, on average, 78% of the amino acids at ligand-binding sites were predicted correctly in the minimum-energy sequences, whereas 84% were predicted correctly in the most-similar sequences, which were selected from the top 20 sequences for each enzyme-ligand complex. Hydrogen bonds at the enzyme-ligand binding interfaces in the 10 complexes were usually recovered with the correct geometries. The binding energies calculated using the combined energy function helped to discriminate the active sequences from a pool of alternative sequences that were generated by repeatedly solving a series of mixed-integer linear programming problems for sequence selection with increasing integer cuts.

The allosteric switching mechanism in bacteriophage MS2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perkett, Matthew R.; Mirijanian, Dina T.; Hagan, Michael F., E-mail: hagan@brandeis.edu

2016-07-21

We use all-atom simulations to elucidate the mechanisms underlying conformational switching and allostery within the coat protein of the bacteriophage MS2. Assembly of most icosahedral virus capsids requires that the capsid protein adopts different conformations at precise locations within the capsid. It has been shown that a 19 nucleotide stem loop (TR) from the MS2 genome acts as an allosteric effector, guiding conformational switching of the coat protein during capsid assembly. Since the principal conformational changes occur far from the TR binding site, it is important to understand the molecular mechanism underlying this allosteric communication. To this end, we usemore » all-atom simulations with explicit water combined with a path sampling technique to sample the MS2 coat protein conformational transition, in the presence and absence of TR-binding. The calculations find that TR binding strongly alters the transition free energy profile, leading to a switch in the favored conformation. We discuss changes in molecular interactions responsible for this shift. We then identify networks of amino acids with correlated motions to reveal the mechanism by which effects of TR binding span the protein. We find that TR binding strongly affects residues located at the 5-fold and quasi-sixfold interfaces in the assembled capsid, suggesting a mechanism by which the TR binding could direct formation of the native capsid geometry. The analysis predicts amino acids whose substitution by mutagenesis could alter populations of the conformational substates or their transition rates.« less

Electrostatic Interactions in Aminoglycoside-RNA Complexes

PubMed Central

Kulik, Marta; Goral, Anna M.; Jasiński, Maciej; Dominiak, Paulina M.; Trylska, Joanna

2015-01-01

Electrostatic interactions often play key roles in the recognition of small molecules by nucleic acids. An example is aminoglycoside antibiotics, which by binding to ribosomal RNA (rRNA) affect bacterial protein synthesis. These antibiotics remain one of the few valid treatments against hospital-acquired infections by Gram-negative bacteria. It is necessary to understand the amplitude of electrostatic interactions between aminoglycosides and their rRNA targets to introduce aminoglycoside modifications that would enhance their binding or to design new scaffolds. Here, we calculated the electrostatic energy of interactions and its per-ring contributions between aminoglycosides and their primary rRNA binding site. We applied either the methodology based on the exact potential multipole moment (EPMM) or classical molecular mechanics force field single-point partial charges with Coulomb formula. For EPMM, we first reconstructed the aspherical electron density of 12 aminoglycoside-RNA complexes from the atomic parameters deposited in the University at Buffalo Databank. The University at Buffalo Databank concept assumes transferability of electron density between atoms in chemically equivalent vicinities and allows reconstruction of the electron densities from experimental structural data. From the electron density, we then calculated the electrostatic energy of interaction using EPMM. Finally, we compared the two approaches. The calculated electrostatic interaction energies between various aminoglycosides and their binding sites correlate with experimentally obtained binding free energies. Based on the calculated energetic contributions of water molecules mediating the interactions between the antibiotic and rRNA, we suggest possible modifications that could enhance aminoglycoside binding affinity. PMID:25650932

DNA binding by a new metallointercalator that contains a proflavine group bearing a hanging chelating unit.

PubMed

Bazzicalupi, Carla; Bencini, Andrea; Bianchi, Antonio; Biver, Tarita; Boggioni, Alessia; Bonacchi, Sara; Danesi, Andrea; Giorgi, Claudia; Gratteri, Paola; Ingraín, Antonio Marchal; Secco, Fernando; Sissi, Claudia; Valtancoli, Barbara; Venturini, Marcella

2008-01-01

The new bifunctional molecule 3,6-diamine-9-[6,6-bis(2-aminoethyl)-1,6-diaminohexyl]acridine (D), which is characterised by both an aromatic moiety and a separate metal-complexing polyamine centre, has been synthesised. The characteristics of D and its ZnII complex ([ZnD]) (protonation and metal-complexing constants, optical properties and self-aggregation phenomena) have been analysed by means of NMR spectroscopy, potentiometric, spectrophotometric and spectrofluorimetric techniques. The equilibria and kinetics of the binding process of D and [ZnD] to calf thymus DNA have been investigated at I=0.11 M (NaCl) and 298.1 K by using spectroscopic methods and the stopped-flow technique. Static measurements show biphasic behaviour for both D-DNA and [ZnD]-DNA systems; this reveals the occurrence of two different binding processes depending on the polymer-to-dye molar ratio (P/D). The binding mode that occurs at low P/D values is interpreted in terms of external binding with a notable contribution from the polyamine residue. The binding mode at high P/D values corresponds to intercalation of the proflavine residue. Stopped-flow, circular dichroism and supercoiled-DNA unwinding experiments corroborate the proposed mechanism. Molecular-modelling studies support the intercalative process and evidence the influence of NH+...O interactions between the protonated acridine nitrogen atom and the oxygen atoms of the polyanion; these interactions play a key role in determining the conformation of DNA adducts.

The allosteric switching mechanism in bacteriophage MS2

PubMed Central

Perkett, Matthew R.; Mirijanian, Dina T.

2016-01-01

We use all-atom simulations to elucidate the mechanisms underlying conformational switching and allostery within the coat protein of the bacteriophage MS2. Assembly of most icosahedral virus capsids requires that the capsid protein adopts different conformations at precise locations within the capsid. It has been shown that a 19 nucleotide stem loop (TR) from the MS2 genome acts as an allosteric effector, guiding conformational switching of the coat protein during capsid assembly. Since the principal conformational changes occur far from the TR binding site, it is important to understand the molecular mechanism underlying this allosteric communication. To this end, we use all-atom simulations with explicit water combined with a path sampling technique to sample the MS2 coat protein conformational transition, in the presence and absence of TR-binding. The calculations find that TR binding strongly alters the transition free energy profile, leading to a switch in the favored conformation. We discuss changes in molecular interactions responsible for this shift. We then identify networks of amino acids with correlated motions to reveal the mechanism by which effects of TR binding span the protein. We find that TR binding strongly affects residues located at the 5-fold and quasi-sixfold interfaces in the assembled capsid, suggesting a mechanism by which the TR binding could direct formation of the native capsid geometry. The analysis predicts amino acids whose substitution by mutagenesis could alter populations of the conformational substates or their transition rates. PMID:27448905

Atomic scale simulations of pyrochlore oxides with a tight-binding variable-charge model: implications for radiation tolerance.

PubMed

Sattonnay, G; Tétot, R

2014-02-05

Atomistic simulations with new interatomic potentials derived from a tight-binding variable-charge model were performed in order to investigate the lattice properties and the defect formation energies in Gd2Ti2O7 and Gd2Zr2O7 pyrochlores. The main objective was to determine the role played by the defect stability on the radiation tolerance of these compounds. Calculations show that the titanate has a more covalent character than the zirconate. Moreover, the properties of oxygen Frenkel pairs, cation antisite defects and cation Frenkel pairs were studied. In Gd2Ti2O7 the cation antisite defect and the Ti-Frenkel pair are not stable: they evolve towards more stable defect configurations during the atomic relaxation process. This phenomenon is driven by a decrease of the Ti coordination number down to five which leads to a local atomic reorganization and strong structural distortions around the defects. These kinds of atomic rearrangements are not observed around defects in Gd2Zr2O7. Therefore, the defect stability in A2B2O7 depends on the ability of B atoms to accommodate high coordination number (higher than six seems impossible for Ti). The accumulation of structural distortions around Ti-defects due to this phenomenon could drive the Gd2Ti2O7 amorphization induced by irradiation.

Subatomic and atomic crystallographic studies of aldose reductase: implications for inhibitor binding.

PubMed

Podjarny, A; Cachau, R E; Schneider, T; Van Zandt, M; Joachimiak, A

2004-04-01

The determination of several of aldose reductase-inhibitor complexes at subatomic resolution has revealed new structural details, including the specific interatomic contacts involved in inhibitor binding. In this article, we review the structures of the complexes of ALR2 with IDD 594 (resolution: 0.66 angstrom, IC50 (concentration of the inhibitor that produced half-maximal effect): 30 nM, space group: P2(1)), IDD 393 (resolution: 0.90 angstrom, IC50: 6 nM, space group: P1), fidarestat (resolution: 0.92 angstrom, IC50: 9 nM, space group: P2(1)) and minalrestat (resolution: 1.10 angstrom, IC50: 73 nM, space group: P1). The structures are compared and found to be highly reproductible within the same space group (root mean square (RMS) deviations: 0.15 approximately 0.3 angstrom). The mode of binding of the carboxylate inhibitors IDD 594 and IDD 393 is analysed. The binding of the carboxylate head can be accurately determined by the subatomic resolution structures, since both the protonation states and the positions of the atoms are very precisely known. The differences appear in the binding in the specificity pocket. The high-resolution structures explain the differences in IC50, which are confirmed both experimentally by mass spectrometry measures of VC50 and theoretically by free energy perturbation calculations. The binding of the cyclic imide inhibitors fidarestat and minalrestat is also described, focusing on the observation of a Cl(-) ion which binds simultaneously with fidarestat. The presence of this anion, binding also to the active site residue His110, leads to a mechanism in which the inhibitor can bind in a neutral state and then become charged inside the active site pocket. This mechanism can explain the excellent in vivo properties of cyclic imide inhibitors. In summary, the complete and detailed information supplied by the subatomic resolution structures can explain the differences in binding energy of the different inhibitors.

Free energy component analysis for drug design: a case study of HIV-1 protease-inhibitor binding.

PubMed

Kalra, P; Reddy, T V; Jayaram, B

2001-12-06

A theoretically rigorous and computationally tractable methodology for the prediction of the free energies of binding of protein-ligand complexes is presented. The method formulated involves developing molecular dynamics trajectories of the enzyme, the inhibitor, and the complex, followed by a free energy component analysis that conveys information on the physicochemical forces driving the protein-ligand complex formation and enables an elucidation of drug design principles for a given receptor from a thermodynamic perspective. The complexes of HIV-1 protease with two peptidomimetic inhibitors were taken as illustrative cases. Four-nanosecond-level all-atom molecular dynamics simulations using explicit solvent without any restraints were carried out on the protease-inhibitor complexes and the free proteases, and the trajectories were analyzed via a thermodynamic cycle to calculate the binding free energies. The computed free energies were seen to be in good accord with the reported data. It was noted that the net van der Waals and hydrophobic contributions were favorable to binding while the net electrostatics, entropies, and adaptation expense were unfavorable in these protease-inhibitor complexes. The hydrogen bond between the CH2OH group of the inhibitor at the scissile position and the catalytic aspartate was found to be favorable to binding. Various implicit solvent models were also considered and their shortcomings discussed. In addition, some plausible modifications to the inhibitor residues were attempted, which led to better binding affinities. The generality of the method and the transferability of the protocol with essentially no changes to any other protein-ligand system are emphasized.

Modeling of flux, binding and substitution of urea molecules in the urea transporter dvUT.

PubMed

Zhang, Hai-Tian; Wang, Zhe; Yu, Tao; Sang, Jian-Ping; Zou, Xian-Wu; Zou, Xiaoqin

2017-09-01

Urea transporters (UTs) are transmembrane proteins that transport urea molecules across cell membranes and play a crucial role in urea excretion and water balance. Modeling the functional characteristics of UTs helps us understand how their structures accomplish the functions at the atomic level, and facilitates future therapeutic design targeting the UTs. This study was based on the crystal structure of Desulfovibrio vulgaris urea transporter (dvUT). To model the binding behavior of urea molecules in dvUT, we constructed a cooperative binding model. To model the substitution of urea by the urea analogue N,N'-dimethylurea (DMU) in dvUT, we calculated the occupation probability of DMU along the urea pore and the ratio of the occupation probabilities of DMU at the external (S ext ) and internal (S int ) binding sites, and we established the mutual substitution rule for binding and substitution of urea and DMU. Based on these calculations and modelings, together with the use of the Monte Carlo (MC) method, we further modeled the urea flux in dvUT, equilibrium urea binding to dvUT, and the substitution of urea by DMU in the dvUT. Our modeling results are in good agreement with the existing experimental functional data. Furthermore, the modelings have discovered the microscopic process and mechanisms of those functional characteristics. The methods and the results would help our future understanding of the underlying mechanisms of the diseases associated with impaired UT functions and rational drug design for the treatment of these diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Atomic-level insights into metabolite recognition and specificity of the SAM-II riboswitch.

PubMed

Doshi, Urmi; Kelley, Jennifer M; Hamelberg, Donald

2012-02-01

Although S-adenosylhomocysteine (SAH), a metabolic by-product of S-adenosylmethionine (SAM), differs from SAM only by a single methyl group and an overall positive charge, SAH binds the SAM-II riboswitch with more than 1000-fold less affinity than SAM. Using atomistic molecular dynamics simulations, we investigated the molecular basis of such high selectivity in ligand recognition by SAM-II riboswitch. The biosynthesis of SAM exclusively generates the (S,S) stereoisomer, and (S,S)-SAM can spontaneously convert to the (R,S) form. We, therefore, also examined the effects of (R,S)-SAM binding to SAM-II and its potential biological function. We find that the unfavorable loss in entropy in SAM-II binding is greater for (S,S)- and (R,S)-SAM than SAH, which is compensated by stabilizing electrostatic interactions with the riboswitch. The positively charged sulfonium moiety on SAM acts as the crucial anchor point responsible for the formation of key ionic interactions as it fits favorably in the negatively charged binding pocket. In contrast, SAH, with its lone pair of electrons on the sulfur, experiences repulsion in the binding pocket of SAM-II and is enthalpically destabilized. In the presence of SAH, similar to the unbound riboswitch, the pseudoknot structure of SAM-II is not completely formed, thus exposing the Shine-Dalgarno sequence. Unlike SAM, this may further facilitate ribosomal assembly and translation initiation. Our analysis of the conformational ensemble sampled by SAM-II in the absence of ligands and when bound to SAM or SAH reveals that ligand binding follows a combination of conformational selection and induced-fit mechanisms.

Monomeric Yeast Frataxin is an Iron-Binding Protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cook,J.; Bencze, K.; Jankovic, A.

Friedreich's ataxia, an autosomal cardio- and neurodegenerative disorder that affects 1 in 50 000 humans, is caused by decreased levels of the protein frataxin. Although frataxin is nuclear-encoded, it is targeted to the mitochondrial matrix and necessary for proper regulation of cellular iron homeostasis. Frataxin is required for the cellular production of both heme and iron-sulfur (Fe-S) clusters. Monomeric frataxin binds with high affinity to ferrochelatase, the enzyme involved in iron insertion into porphyrin during heme production. Monomeric frataxin also binds to Isu, the scaffold protein required for assembly of Fe-S cluster intermediates. These processes (heme and Fe-S cluster assembly)more » share requirements for iron, suggesting that monomeric frataxin might function as the common iron donor. To provide a molecular basis to better understand frataxin's function, we have characterized the binding properties and metal-site structure of ferrous iron bound to monomeric yeast frataxin. Yeast frataxin is stable as an iron-loaded monomer, and the protein can bind two ferrous iron atoms with micromolar binding affinity. Frataxin amino acids affected by the presence of iron are localized within conserved acidic patches located on the surfaces of both helix-1 and strand-1. Under anaerobic conditions, bound metal is stable in the high-spin ferrous state. The metal-ligand coordination geometry of both metal-binding sites is consistent with a six-coordinate iron-(oxygen/nitrogen) based ligand geometry, surely constructed in part from carboxylate and possibly imidazole side chains coming from residues within these conserved acidic patches on the protein. On the basis of our results, we have developed a model for how we believe yeast frataxin interacts with iron.« less

Monomeric Yeast Frataxin is an Iron Binding Protein†

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cook, J.; Bencze, K; Jankovic, A

Friedreich's ataxia, an autosomal cardio- and neurodegenerative disorder that affects 1 in 50000 humans, is caused by decreased levels of the protein frataxin. Although frataxin is nuclear-encoded, it is targeted to the mitochondrial matrix and necessary for proper regulation of cellular iron homeostasis. Frataxin is required for the cellular production of both heme and iron-sulfur (Fe-S) clusters. Monomeric frataxin binds with high affinity to ferrochelatase, the enzyme involved in iron insertion into porphyrin during heme production. Monomeric frataxin also binds to Isu, the scaffold protein required for assembly of Fe-S cluster intermediates. These processes (heme and Fe-S cluster assembly) sharemore » requirements for iron, suggesting that monomeric frataxin might function as the common iron donor. To provide a molecular basis to better understand frataxin's function, we have characterized the binding properties and metal-site structure of ferrous iron bound to monomeric yeast frataxin. Yeast frataxin is stable as an iron-loaded monomer, and the protein can bind two ferrous iron atoms with micromolar binding affinity. Frataxin amino acids affected by the presence of iron are localized within conserved acidic patches located on the surfaces of both helix-1 and strand-1. Under anaerobic conditions, bound metal is stable in the high-spin ferrous state. The metal-ligand coordination geometry of both metal-binding sites is consistent with a six-coordinate iron-(oxygen/nitrogen) based ligand geometry, surely constructed in part from carboxylate and possibly imidazole side chains coming from residues within these conserved acidic patches on the protein. On the basis of our results, we have developed a model for how we believe yeast frataxin interacts with iron.« less

Small Vacuum Compatible Hyperthermal Atom Generator

NASA Technical Reports Server (NTRS)

Outlaw, Ronald A. (Inventor); Davidson, Mark R. (Inventor)

1998-01-01

A vacuum compatible hyperthermal atom generator includes a membrane having two sides. the membrane having the capability of dissolving atoms into the membrane's bulk. A first housing is furnished in operative association with the first side of the membrane to provide for the exposure of the first side of the membrane to a gas species. A second housing is furnished in operative association with the second side of the membrane to provide a vacuum environment having a pressure of less than 1 x 10(exp -3) Torr on the second side of the membrane. Exciting means excites atoms adsorbed on the second side of the membrane to a non-binding state so that a portion from 0% to 100% of atoms adsorbed on the second side of is the membrane are released from the second side of the membrane primarily as an atom beam.

Silver clusters encapsulated in C{sub 60}: A density functional study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dhiman, Shobhna; Kumar, Ranjan; Dharamvir, Keya

2015-08-28

We explore the possibility of formation of endohedral complexes of Ag{sub n} atoms (n=1-9) inside C{sub 60} molecule using density functional theory and molecular dynamics. The obtained results reveal that Ag{sub n} (n=8) atoms can form stable complexes with the C{sub 60} molecule. Encapsulation of large number of Ag{sub n} atoms (n>8) make C{sub 60} cage instable, showing distortion of cage. Binding energy/atom increases with the number of Ag atoms up to n=4, after that it increases. Ionization potential decreases till n=4 and then increases, electron affinity increases till n=4 and then shows oscillatory nature as a function of Agmore » atoms inside the cage. Homo –Lumo gap shows no systematic pattern. Our results agreed well with the data available.« less

Low temperature scanning tunneling microscopy of metallic and organic nanostructures

NASA Astrophysics Data System (ADS)

Fölsch, Stefan

2006-03-01

Low temperature scanning tunneling microscopy (LT-STM) is capable of both characterizing and manipulating atomic-scale structures at surfaces. It thus provides a powerful experimental tool to gain fundamental insight into how electronic properties evolve when controlling size, geometry, and composition of nanometric model systems at the level of single atoms and molecules. The experiments discussed in this talk employ a Cu(111) surface onto which perfect nanostructures are assembled from native adatoms and organic molecules. Using single Cu adatoms as building blocks, we obtain zero-, one-, and two-dimensional quantum objects (corresponding to the discrete adatom, monatomic adatom chains, and compact adatom assemblies) with intriguing electronic properties. Depending on the structure shape and the number of incorporated atoms we observe the formation of characteristic quantum levels which merge into the sp-derived Shockley surface state in the limit of extended 2D islands; this state exists on many surfaces, such as Cu(111). Our results reveal the natural linkage between this traditional surface property, the quantum confinement in compact adatom structures, and the quasi-atomic state associated with the single adatom. In a second step, we study the interaction of pentacene (C22H14) with Cu adatom chains serving as model quantum wires. We find that STM-based manipulation is capable of connecting single molecules to the chain ends in a defined way, and that the molecule-chain interaction shifts the chain-localized quantum states to higher binding energies. The present system provides an instructive model case to study single organic molecules interacting with metallic nanostructures. The microscopic nature of such composite structures is of importance for any future molecular-based device realization since it determines the contact conductance between the molecular unit and its metal ''contact pad''.

Binding Mechanisms of Intrinsically Disordered Proteins: Theory, Simulation, and Experiment

PubMed Central

Mollica, Luca; Bessa, Luiza M.; Hanoulle, Xavier; Jensen, Malene Ringkjøbing; Blackledge, Martin; Schneider, Robert

2016-01-01

In recent years, protein science has been revolutionized by the discovery of intrinsically disordered proteins (IDPs). In contrast to the classical paradigm that a given protein sequence corresponds to a defined structure and an associated function, we now know that proteins can be functional in the absence of a stable three-dimensional structure. In many cases, disordered proteins or protein regions become structured, at least locally, upon interacting with their physiological partners. Many, sometimes conflicting, hypotheses have been put forward regarding the interaction mechanisms of IDPs and the potential advantages of disorder for protein-protein interactions. Whether disorder may increase, as proposed, e.g., in the “fly-casting” hypothesis, or decrease binding rates, increase or decrease binding specificity, or what role pre-formed structure might play in interactions involving IDPs (conformational selection vs. induced fit), are subjects of intense debate. Experimentally, these questions remain difficult to address. Here, we review experimental studies of binding mechanisms of IDPs using NMR spectroscopy and transient kinetic techniques, as well as the underlying theoretical concepts and numerical methods that can be applied to describe these interactions at the atomic level. The available literature suggests that the kinetic and thermodynamic parameters characterizing interactions involving IDPs can vary widely and that there may be no single common mechanism that can explain the different binding modes observed experimentally. Rather, disordered proteins appear to make combined use of features such as pre-formed structure and flexibility, depending on the individual system and the functional context. PMID:27668217

Electrochemistry of Metal Surfaces

DTIC Science & Technology

1990-06-30

i) 3-pyridine carboxylic acid ( nicotinic acid, NA) binds to Pt surfaces through both the nitrogen atom and an oxygen atom of the carboxylate group...formed from aqueous electrolytes at Pt(1l1) electrode surfaces have been compared with the IR and Raman spectra of the unadsorbed compounds in order...vibrational absorptivities between EELS spectra of adsorbed species and IR and Raman spectra of the corresponding unadsorbed compounds (146). Of

Macrocycles inserted in graphene: from coordination chemistry on graphene to graphitic carbon oxide.

NASA Astrophysics Data System (ADS)

Liu, Wei; Liu, Jingyao; Miao, Maosheng

Tuning the electronic structure and the chemical properties of graphene by binding with metals has become a focus in the area of two dimension materials. Despite many interesting results and promising potentials, the approach suffers from weak binding and the high reactivity of the metal atoms. On the other hand, many macrocyclic molecules such as crown ether show strong and selective binding with metal atoms. The alliance of the two substances will largely benefit the two parallel fields: it will provide a scaffold for coordination chemistry as well as a controllable method for tuning the electronic structure of graphene through strong binding with metals. Here, using crown ether as an example, we demonstrate by first principles calculations that the embedment of macrocyclic molecules into graphene honeycomb lattice can be very thermochemically favored. The embedment of crown ether on graphene can form a family of new two-dimensional materials that possess varying band gaps and band edges. The one with highest O composition (C2O), with similar structure features as graphilic C3N4, shows strong potentials for photolysis and as true two-dimensional superconductor while binding with alkali metals. Calculations are performed on NSF-funded XSEDE resources (TG-DMR130005). This research is also supported by National Natural Science Foundation of China (Grants No. 21373098) in China.

Energetic stabilities of thiolated pyrimidines on gold nanoparticles investigated by Raman spectroscopy and density functional theory calculations.

PubMed

Ganbold, Erdene-Ochir; Yoon, Jinha; Cho, Kwang-Hwi; Joo, Sang-Woo

2015-01-01

The adsorption structures of 2-thiocytosine (2TC) on gold surfaces were examined by means of vibrational Raman spectroscopy and quantum mechanical density functional theory calculations. The 1H-thione-amino form was calculated to be most stable among the six examined tautomers. The three plausible binding geometries of sulfur, pyrimidine nitrogen, and amino group binding modes were calculated to estimate the binding energies of the 1H-thione-amino form with six gold cluster atoms. Thiouracils including 2-thiouracil (2TU), 4-thiouracil (4TU), and 6-methyl-2-thiouracil (6M2TU) were also studied to compare their relative binding energies on gold atoms. The intracellular localization of a DNA base analog of 2TC on gold nanoparticles (AuNPs) in HeLa cells was identified by means of surface-enhanced Raman scattering. AuNPs were modified with 2TC by self-assembly. Our dark-field microscopy and z-depth-dependent confocal Raman spectroscopy indicated that 2TC-assembled AuNPs could be found inside cancer cells. On the other hand, we did not observe noticeably strong Raman peaks in the cases of thiouracils including 2TU, 4TU, and 6M2TU. This may be due to the additional amino group of 2TC, which can lead to a stronger binding of adsorbates on AuNPs. Copyright © 2015. Published by Elsevier B.V.

Role of hydrogen bonding in ligand interaction with the N-methyl-D-aspartate receptor ion channel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leeson, P.D.; Carling, R.W.; James, K.

1990-05-01

Displacement of (3H)MK-801 (dizocilpine, 1) binding to rat brain membranes has been used to evaluate the affinities of novel dibenzocycloalkenimines related to 1 for the ion channel binding site (also known as the phencyclidine or PCP receptor) on the N-methyl-D-aspartate (NMDA) subtype of excitory amino acid receptor. In common with many other agents having actions in the central nervous system, these compounds contain a hydrophobic aromatic moiety and a basic nitrogen atom. The conformational rigidity of these ligands provides a unique opportunity to evaluate the importance of specific geometrical properties that influence active-site recognition, in particular the role of themore » nitrogen atom in hydrogen-bonding interactions. The relative affinities (IC50s) of hydrocarbon-substituted analogues of 1 and ring homologated cyclooctenimines illustrate the importance of size-limited hydrophobic binding of both aryl rings and of the quaternary C-5 methyl group. Analysis of the binding of a series of the 10 available structurally rigid dibenzoazabicyclo(x.y.z)alkanes, by using molecular modeling techniques, uncovered a highly significant correlation between affinity and a proposed ligand-active site hydrogen bonding vector (r = 0.950, p less than 0.001). These results are used to generate a pharmacophore of the MK-801 recognition site/PCP receptor, which accounts for the binding of all of the known ligands.« less

Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds.

PubMed

Giroud, Maude; Harder, Michael; Kuhn, Bernd; Haap, Wolfgang; Trapp, Nils; Schweizer, W Bernd; Schirmeister, Tanja; Diederich, François

2016-05-19

The π-stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme-ligand binding studies complemented by high-level quantum chemical calculations. In the experimental study, the phenyl substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by additional interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calculations strongly support the contributions of the molecular quadrupole moments of the fluorinated phenyl rings to the π-stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π-stacking on protein amide fragments. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Thermally induced anchoring of a zinc-carboxyphenylporphyrin on rutile TiO2 (110)

NASA Astrophysics Data System (ADS)

Jöhr, Res; Hinaut, Antoine; Pawlak, Rémy; Zajac, Łukasz; Olszowski, Piotr; Such, Bartosz; Glatzel, Thilo; Zhang, Jun; Muntwiler, Matthias; Bergkamp, Jesse J.; Mateo, Luis-Manuel; Decurtins, Silvio; Liu, Shi-Xia; Meyer, Ernst

2017-05-01

Functionalization of surfaces has become of high interest for a wealth of applications such as sensors, hybrid photovoltaics, catalysis, and molecular electronics. Thereby molecule-surface interactions are of crucial importance for the understanding of interface properties. An especially relevant point is the anchoring of molecules to surfaces. In this work, we analyze this process for a zinc-porphyrin equipped with carboxylic acid anchoring groups on rutile TiO2 (110) using scanning probe microscopy. After evaporation, the porphyrins are not covalently bound to the surface. Upon annealing, the carboxylic acid anchors undergo deprotonation and bind to surface titanium atoms. The formation of covalent bonds is evident from the changed stability of the molecule on the surface as well as the adsorption configuration. Annealed porphyrins are rotated by 45° and adopt another adsorption site. The influence of binding on electronic coupling with the surface is investigated using photoelectron spectroscopy. The observed shifts of Zn 2p and N 1s levels to higher binding energies indicate charging of the porphyrin core, which is accompanied by a deformation of the macrocycle due to a strong interaction with the surface.

Atmospheric pollutants in fog and rain events at the northwestern mountains of the Iberian Peninsula.

PubMed

Fernández-González, Ricardo; Yebra-Pimentel, Iria; Martínez-Carballo, Elena; Simal-Gándara, Jesús; Pontevedra-Pombal, Xabier

2014-11-01

Atmospheric polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) and exist in gas and particle phases, as well as dissolved or suspended in precipitation (fog or rain). While the hydrosphere is the main reservoir for PAHs, the atmosphere serves as the primary route for global transport of PCBs. In this study, fog and rain samples were collected during fourteen events from September 2011 to April 2012 in the Xistral Mountains, a remote range in the NW Iberian Peninsula. PAH compounds [especially of low molecular weight (LMW)] were universally found, but mainly in the fog-water samples. The total PAH concentration in fog-water ranged from non-detected to 216 ng·L(-1) (mean of 45 ng·L(-1)), and was much higher in fall than in winter. Total PAH levels in the rain and fog events varied from non-detected to 1272 and 33 ng·L(-1) for, respectively, LMW and high molecular weight (HMW) PAHs. Diagnostic ratio analysis (LMW PAHs/HMW PAHs) suggested that petroleum combustion was the dominant contributor to PAHs in the area. Total PCB levels in the rain and fog events varied from non-detected to 305 and 91 ng·L(-1) for, respectively, PCBs with 2-3 Cl atoms and 5-10 Cl atoms. PCBs, especially those with 5-10 Cl atoms, were found linked to rain events. The occurrence of the most volatile PCBs, PCBs with 2-3 Cl atoms, is related to wind transport from far away sources, whereas the occurrence of PCBs with 5-10 Cl atoms seems to be related with the increase of its deposition during rainfall at the end of summer and fall. The movement of this fraction of PCBs is facilitated by its binding to air-suspended particles, whose concentrations usually show an increase as the result of a prolonged period of drought in summer. Copyright © 2014 Elsevier B.V. All rights reserved.

Insights on the mechanism of action of immunostimulants in relation to their pharmacological potency. The effects of imidazoquinolines on TLR8.

PubMed

Kubli-Garfias, Carlos; Vázquez-Ramírez, Ricardo; Trejo-Muñoz, Cynthia; Berber, Arturo

2017-01-01

Imidazoquinolines are powerful immunostimulants (IMMS) that function through Toll-like receptors, particularly TLR7 and TLR8. In addition to enhancing the immune response, IMMS also function as antineoplastic drugs and vaccine adjuvants. These small compounds display almost the same molecular structure, except in some cases in which atom in position 1 varies and changes the imidazole characteristics. A variable acyclic side chain is also always attached at atom in position 2, while another chain may be attached at atom in position 1. These structural differences alter immune responses, such as the production of interferon regulatory factor and nuclear factor-κB (IRF-NFκB). In this work, quantum mechanics theory and computational chemistry methods were applied to study the physicochemical properties of the crystal binding site of TLR8 complexed with the following six IMMS molecules: Hybrid-2, XG1-236, DS802, CL075, CL097 and R848 (resiquimod). The PDB IDs of the crystals were: 4R6A, 4QC0, 4QBZ, 3W3K, 3W3J, and 3W3N respectively. Thus, were calculated, the total energy, solvation energy, interaction energy (instead of free energy) of the system and interaction energy of the polar region of the IMMS. Additionally, the dipole moment, electrostatic potential, polar surface, atomic charges, hydrogen bonds, and polar and hydrophobic interactions, among others, were assessed. Together, these properties revealed important differences among the six TLR8-immunostimulant complexes, reflected as different interaction energies and therefore different electrostatic environments and binding energies. Remarkably, the interaction energy of a defined polar region composed of the highly polarized N3, N5 atoms and the N11 amino group, acted as a polar pharmacophore that correlates directly with the reported immunopharmacological potency of the six complexed molecules. Based on these results, it was concluded that accurate physicochemical analysis of the crystal binding site could reveal the binding energy (measured as interaction energy) and associated molecular mechanism of action between IMMS and TLR8. These findings may facilitate the development and design of improved small molecules with IMMS properties that are targeted to the TLR system and have enhanced pharmacological effectiveness and reduced toxicity.

Insights on the mechanism of action of immunostimulants in relation to their pharmacological potency. The effects of imidazoquinolines on TLR8

PubMed Central

Kubli-Garfias, Carlos; Vázquez-Ramírez, Ricardo; Trejo-Muñoz, Cynthia; Berber, Arturo

2017-01-01

Imidazoquinolines are powerful immunostimulants (IMMS) that function through Toll-like receptors, particularly TLR7 and TLR8. In addition to enhancing the immune response, IMMS also function as antineoplastic drugs and vaccine adjuvants. These small compounds display almost the same molecular structure, except in some cases in which atom in position 1 varies and changes the imidazole characteristics. A variable acyclic side chain is also always attached at atom in position 2, while another chain may be attached at atom in position 1. These structural differences alter immune responses, such as the production of interferon regulatory factor and nuclear factor-κB (IRF-NFκB). In this work, quantum mechanics theory and computational chemistry methods were applied to study the physicochemical properties of the crystal binding site of TLR8 complexed with the following six IMMS molecules: Hybrid-2, XG1-236, DS802, CL075, CL097 and R848 (resiquimod). The PDB IDs of the crystals were: 4R6A, 4QC0, 4QBZ, 3W3K, 3W3J, and 3W3N respectively. Thus, were calculated, the total energy, solvation energy, interaction energy (instead of free energy) of the system and interaction energy of the polar region of the IMMS. Additionally, the dipole moment, electrostatic potential, polar surface, atomic charges, hydrogen bonds, and polar and hydrophobic interactions, among others, were assessed. Together, these properties revealed important differences among the six TLR8-immunostimulant complexes, reflected as different interaction energies and therefore different electrostatic environments and binding energies. Remarkably, the interaction energy of a defined polar region composed of the highly polarized N3, N5 atoms and the N11 amino group, acted as a polar pharmacophore that correlates directly with the reported immunopharmacological potency of the six complexed molecules. Based on these results, it was concluded that accurate physicochemical analysis of the crystal binding site could reveal the binding energy (measured as interaction energy) and associated molecular mechanism of action between IMMS and TLR8. These findings may facilitate the development and design of improved small molecules with IMMS properties that are targeted to the TLR system and have enhanced pharmacological effectiveness and reduced toxicity. PMID:28582454

Chemical conversion of cisplatin and carboplatin with histidine in a model protein crystallized under sodium iodide conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tanley, Simon W. M.; Helliwell, John R., E-mail: john.helliwell@manchester.ac.uk

Crystals of HEWL with cisplatin and HEWL with carboplatin grown in sodium iodide conditions both show a partial chemical transformation of cisplatin or carboplatin to a transiodoplatin (PtI{sub 2}X{sub 2}) form. The binding is only at the N{sup δ} atom of His15. A further Pt species (PtI{sub 3}X) is also seen, in both cases bound in a crevice between symmetry-related protein molecules. Cisplatin and carboplatin are platinum anticancer agents that are used to treat a variety of cancers. Previous X-ray crystallographic studies of carboplatin binding to histidine in hen egg-white lysozyme (HEWL) showed a partial chemical conversion of carboplatin tomore » cisplatin owing to the high sodium chloride concentration used in the crystallization conditions. Also, the co-crystallization of HEWL with carboplatin in sodium bromide conditions resulted in the partial conversion of carboplatin to the transbromoplatin form, with a portion of the cyclobutanedicarboxylate (CBDC) moiety still present. The results of the co-crystallization of HEWL with cisplatin or carboplatin in sodium iodide conditions are now reported in order to determine whether the cisplatin and carboplatin converted to the iodo form, and whether this took place in a similar way to the partial conversion of carboplatin to cisplatin in NaCl conditions or to transbromoplatin in NaBr conditions as seen previously. It is reported here that a partial chemical transformation has taken place to a transplatin form for both ligands. The NaI-grown crystals belonged to the monoclinic space group P2{sub 1} with two molecules in the asymmetric unit. The chemically transformed cisplatin and carboplatin bind to both His15 residues, i.e. in each asymmetric unit. The binding is only at the N{sup δ} atom of His15. A third platinum species is also seen in both conditions bound in a crevice between symmetry-related molecules. Here, the platinum is bound to three I atoms identified based on their anomalous difference electron densities and their refined occupancies, with the fourth bound atom being a Cl atom (in the cisplatin case) or a portion of the CBDC moiety (in the carboplatin case)« less

A computational ab initio study of surface diffusion of sulfur on the CdTe (111) surface

NASA Astrophysics Data System (ADS)

Naderi, Ebadollah; Ghaisas, S. V.

2016-08-01

In order to discern the formation of epitaxial growth of CdS shell over CdTe nanocrystals, kinetics related to the initial stages of the growth of CdS on CdTe is investigated using ab-initio methods. We report diffusion of sulfur adatom on the CdTe (111) A-type (Cd-terminated) and B-type (Te-terminated) surfaces within the density functional theory (DFT). The barriers are computed by applying the climbing Nudge Elastic Band (c-NEB) method. From the results surface hopping emerges as the major mode of diffusion. In addition, there is a distinct contribution from kick-out type diffusion in which a CdTe surface atom is kicked out from its position and is replaced by the diffusing sulfur atom. Also, surface vacancy substitution contributes to the concomitant dynamics. There are sites on the B- type surface that are competitively close in terms of the binding energy to the lowest energy site of epitaxy on the surface. The kick-out process is more likely for B-type surface where a Te atom of the surface is displaced by a sulfur adatom. Further, on the B-type surface, subsurface migration of sulfur is indicated. Furthermore, the binding energies of S on CdTe reveal that on the A-type surface, epitaxial sites provide relatively higher binding energies and barriers than on B-type.

A computational ab initio study of surface diffusion of sulfur on the CdTe (111) surface

DOE Office of Scientific and Technical Information (OSTI.GOV)

Naderi, Ebadollah, E-mail: enaderi42@gmail.com; Ghaisas, S. V.

2016-08-15

In order to discern the formation of epitaxial growth of CdS shell over CdTe nanocrystals, kinetics related to the initial stages of the growth of CdS on CdTe is investigated using ab-initio methods. We report diffusion of sulfur adatom on the CdTe (111) A-type (Cd-terminated) and B-type (Te-terminated) surfaces within the density functional theory (DFT). The barriers are computed by applying the climbing Nudge Elastic Band (c-NEB) method. From the results surface hopping emerges as the major mode of diffusion. In addition, there is a distinct contribution from kick-out type diffusion in which a CdTe surface atom is kicked outmore » from its position and is replaced by the diffusing sulfur atom. Also, surface vacancy substitution contributes to the concomitant dynamics. There are sites on the B- type surface that are competitively close in terms of the binding energy to the lowest energy site of epitaxy on the surface. The kick-out process is more likely for B-type surface where a Te atom of the surface is displaced by a sulfur adatom. Further, on the B-type surface, subsurface migration of sulfur is indicated. Furthermore, the binding energies of S on CdTe reveal that on the A-type surface, epitaxial sites provide relatively higher binding energies and barriers than on B-type.« less

Atomic model of a cell-wall cross-linking enzyme in complex with an intact bacterial peptidoglycan.

PubMed

Schanda, Paul; Triboulet, Sébastien; Laguri, Cédric; Bougault, Catherine M; Ayala, Isabel; Callon, Morgane; Arthur, Michel; Simorre, Jean-Pierre

2014-12-24

The maintenance of bacterial cell shape and integrity is largely attributed to peptidoglycan, a highly cross-linked biopolymer. The transpeptidases that perform this cross-linking are important targets for antibiotics. Despite this biomedical importance, to date no structure of a protein in complex with an intact bacterial peptidoglycan has been resolved, primarily due to the large size and flexibility of peptidoglycan sacculi. Here we use solid-state NMR spectroscopy to derive for the first time an atomic model of an l,d-transpeptidase from Bacillus subtilis bound to its natural substrate, the intact B. subtilis peptidoglycan. Importantly, the model obtained from protein chemical shift perturbation data shows that both domains-the catalytic domain as well as the proposed peptidoglycan recognition domain-are important for the interaction and reveals a novel binding motif that involves residues outside of the classical enzymatic pocket. Experiments on mutants and truncated protein constructs independently confirm the binding site and the implication of both domains. Through measurements of dipolar-coupling derived order parameters of bond motion we show that protein binding reduces the flexibility of peptidoglycan. This first report of an atomic model of a protein-peptidoglycan complex paves the way for the design of new antibiotic drugs targeting l,d-transpeptidases. The strategy developed here can be extended to the study of a large variety of enzymes involved in peptidoglycan morphogenesis.

Curcumin Inhibits Tau Aggregation and Disintegrates Preformed Tau Filaments in vitro.

PubMed

Rane, Jitendra Subhash; Bhaumik, Prasenjit; Panda, Dulal

2017-01-01

The pathological aggregation of tau is a common feature of most of the neuronal disorders including frontotemporal dementia, Parkinson's disease, and Alzheimer's disease. The inhibition of tau aggregation is considered to be one of the important strategies for treating these neurodegenerative diseases. Curcumin, a natural polyphenolic molecule, has been reported to have neuroprotective ability. In this work, curcumin was found to bind to adult tau and fetal tau with a dissociation constant of 3.3±0.4 and 8±1 μM, respectively. Molecular docking studies indicated a putative binding site of curcumin in the microtubule-binding region of tau. Using several complementary techniques, including dynamic light scattering, thioflavin S fluorescence, 90° light scattering, electron microscopy, and atomic force microscopy, curcumin was found to inhibit the aggregation of tau. The dynamic light scattering analysis and atomic force microscopic images revealed that curcumin inhibits the oligomerization of tau. Curcumin also disintegrated preformed tau oligomers. Using Far-UV circular dichroism, curcumin was found to inhibit the β-sheets formation in tau indicating that curcumin inhibits an initial step of tau aggregation. In addition, curcumin inhibited tau fibril formation. Furthermore, the effect of curcumin on the preformed tau filaments was analyzed by atomic force microscopy, transmission electron microscopy, and 90° light scattering. Curcumin treatment disintegrated preformed tau filaments. The results indicated that curcumin inhibited the oligomerization of tau and could disaggregate tau filaments.

Molecular modeling on structure-function analysis of human progesterone receptor modulators.

PubMed

Pal, Ria; Islam, Md Ataul; Hossain, Tabassum; Saha, Achintya

2011-01-01

Considering the significance of progesterone receptor (PR) modulators, the present study is explored to envisage the biophoric signals for binding to selective PR subtype-A using ligand-based quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies on nonsteroidal substituted quinoline and cyclocymopol monomethyl ether derivatives. Consensus QSAR models (Training set (Tr): n(Tr)=100, R(2) (pred)=0.702; test set (Ts): n(Ts)=30, R(2) (pred)=0.705, R(2) (m)=0.635; validation set (Vs): n(Vs)=40, R(2) (pred)=0.715, R(2) (m)=0.680) suggest that molecular topology, atomic polarizability and electronegativity, atomic mass and van der Waals volume of the ligands have influence on the presence of functional atoms (F, Cl, N and O) and consequently contribute significant relations on ligand binding affinity. Receptor independent space modeling study (Tr: n(Tr)=26, Q(2)=0.927; Ts: n(Ts)=60, R(2) (pred)=0.613, R(2) (m)=0.545; Vs: n(Vs)=84, R(2) (pred)=0.611, R(2) (m)=0.507) indicates the importance of aromatic ring, hydrogen bond donor, molecular hydrophobicity and steric influence for receptor binding. The structure-function characterization is adjudged with the receptor-based docking study, explaining the significance of the mapped molecular attributes for ligand-receptor interaction in the catalytic cleft of PR-A.

The Study of the Successive Metal-ligand Binding Energies for Fe(+), Fe(-), V(+) and Co(+)

NASA Technical Reports Server (NTRS)

Bauschlicher, Charles W., Jr.; Ricca, Alessandra; Maitre, Philippe; Langhoff, Stephen R. (Technical Monitor)

1994-01-01

The successive binding energies of CO and H2O to Fe(+), CO to Fe(-), and H2 to Co(+) and V(+) are presented. Overall the computed results are in good agreement with experiment. The trends in binding energies are analyzed in terms of metal to ligand donation, ligand to metal donation, ligand-ligand repulsion, and changes in the metal atom, such as hybridization, promotion, and spin multiplicity. The geometry and vibrational frequencies are also shown to be directly affected by these effects.

The Study Of The Successive Metal-Ligand Binding Energies For Fe+, Fe-, V+ and Co+

NASA Technical Reports Server (NTRS)

Bauschicher, Charles W., Jr.; Ricca, Alessandra; Maitre, Philippe; Langhoff, Stephen R. (Technical Monitor)

1995-01-01

The successive binding energies of CO and H2O to Fe(+), CO to Fe(-), and H2 to Co(+) and V(+) are presented. Overall the computed results are in good agreement with experiment. The trends in binding energies are analyzed in terms of metal to ligand donation, ligand to metal donation, ligand-ligand repulsion, and changes in the metal atom, such as hybridization, promotion, and spin multiplicity. The geometry and vibrational frequencies are also shown to be directly affected by these effects.

How does huperzine A enter and leave the binding gorge of acetylcholinesterase? Steered molecular dynamics simulations.

PubMed

Xu, Yechun; Shen, Jianhua; Luo, Xiaomin; Silman, Israel; Sussman, Joel L; Chen, Kaixian; Jiang, Hualiang

2003-09-17

The entering and leaving processes of Huperzine A (HupA) binding with the long active-site gorge of Torpedo californica acetylcholinesterase (TcAChE) have been investigated by using steered molecular dynamics simulations. The analysis of the force required along the pathway shows that it is easier for HupA to bind to the active site of AChE than to disassociate from it, which for the first time interprets at the atomic level the previous experimental result that unbinding process of HupA is much slower than its binding process to AChE. The direct hydrogen bonds, water bridges, and hydrophobic interactions were analyzed during two steered molecular dynamics (SMD) simulations. Break of the direct hydrogen bond needs a great pulling force. The steric hindrance of bottleneck might be the most important factor to produce the maximal rupture force for HupA to leave the binding site but it has a little effect on the binding process of HupA with AChE. Residue Asp72 forms a lot of water bridges with HupA leaving and entering the AChE binding gorge, acting as a clamp to take out HupA from or put HupA into the active site. The flip of the peptide bond between Gly117 and Gly118 has been detected during both the conventional MD and SMD simulations. The simulation results indicate that this flip phenomenon could be an intrinsic property of AChE and the Gly117-Gly118 peptide bond in both HupA bound and unbound AChE structures tends to adopt the native enzyme structure. At last, in a vacuum the rupture force is increased up to 1500 pN while in water solution the greatest rupture force is about 800 pN, which means water molecules in the binding gorge act as lubricant to facilitate HupA entering or leaving the binding gorge.

Covalent bonds are created by the drive of electron waves to lower their kinetic energy through expansion

PubMed Central

Schmidt, Michael W.; Ivanic, Joseph; Ruedenberg, Klaus

2014-01-01

An analysis based on the variation principle shows that in the molecules H2+, H2, B2, C2, N2, O2, F2, covalent bonding is driven by the attenuation of the kinetic energy that results from the delocalization of the electronic wave function. For molecular geometries around the equilibrium distance, two features of the wave function contribute to this delocalization: (i) Superposition of atomic orbitals extends the electronic wave function from one atom to two or more atoms; (ii) intra-atomic contraction of the atomic orbitals further increases the inter-atomic delocalization. The inter-atomic kinetic energy lowering that (perhaps counter-intuitively) is a consequence of the intra-atomic contractions drives these contractions (which per se would increase the energy). Since the contractions necessarily encompass both, the intra-atomic kinetic and potential energy changes (which add to a positive total), the fact that the intra-atomic potential energy change renders the total potential binding energy negative does not alter the fact that it is the kinetic delocalization energy that drives the bond formation. PMID:24880263

Covalent bonds are created by the drive of electron waves to lower their kinetic energy through expansion.

PubMed

Schmidt, Michael W; Ivanic, Joseph; Ruedenberg, Klaus

2014-05-28

An analysis based on the variation principle shows that in the molecules H2 (+), H2, B2, C2, N2, O2, F2, covalent bonding is driven by the attenuation of the kinetic energy that results from the delocalization of the electronic wave function. For molecular geometries around the equilibrium distance, two features of the wave function contribute to this delocalization: (i) Superposition of atomic orbitals extends the electronic wave function from one atom to two or more atoms; (ii) intra-atomic contraction of the atomic orbitals further increases the inter-atomic delocalization. The inter-atomic kinetic energy lowering that (perhaps counter-intuitively) is a consequence of the intra-atomic contractions drives these contractions (which per se would increase the energy). Since the contractions necessarily encompass both, the intra-atomic kinetic and potential energy changes (which add to a positive total), the fact that the intra-atomic potential energy change renders the total potential binding energy negative does not alter the fact that it is the kinetic delocalization energy that drives the bond formation.

Influence of bending of monoatomic copper chains with 10 and 22 atoms on their absorbance spectra: TD-DFT calculations

NASA Astrophysics Data System (ADS)

Markin, Alexey V.; Skaptsov, Alexander A.; Markina, Natalia E.

2018-04-01

The aim of the work is the investigation of bending on the properties of hypothetical one-atom-thick copper clusters (CC) (with 10 and 22 atoms). Time-dependent density functional theory with PBE0 functional and lanl2dz basis set were used for all calculations. The bending was performed by changing angle between copper atoms from 180° to 144° and 163.7° (2° step size) for CC with 10 and 22 atoms, correspondingly. The dependences of absorbance spectra in UVvisible-NIR range (400-2000 nm range) and various energetic characteristics (final energy, chemical potential, and binding energy) on bending angle were investigated. Non-bended (linear) clusters were assigned as references. First, absorbance spectra of all CC contain interband transitions (3d->4sp) in UV-visible range (below 600 nm). Linear configuration of CC also contain intensive absorbance band in NIR region (at 900 and 1700 nm for CC with 10 and 22 atoms) which is associated with 4s electron oscillations along clusters (longitudinal transitions). Significant dumping of low energy 4s transitions (HOMO->LUMO) and interband transitions in the range 600‒500 nm was observed during the bending of CC. Obtained results are in agreement with experimental results for 2D copper nanostructures from literature. We explain such influence of bending by formation merging 4s orbitals which form new 4s oscillations in-plane of bending (in the case of ring-like CC - diametral oscillations). An influence of bending on energy, stability, and chemical potential (Fermi level) of CC was also investigated and discussed.

Docking model of the nicotinic acetylcholine receptor and nitromethylene neonicotinoid derivatives with a longer chiral substituent and their biological activities.

PubMed

Nagaoka, Hikaru; Nishiwaki, Hisashi; Kubo, Takuya; Akamatsu, Miki; Yamauchi, Satoshi; Shuto, Yoshihiro

2015-02-15

In the present study, nitromethylene neonicotinoid derivatives possessing substituents that contain a sulfur atom, oxygen atom or aromatic ring at position 5 on the imidazolidine ring were synthesized to evaluate their affinity for the nicotinic acetylcholine receptor (nAChR) and their insecticidal activity against adult female houseflies. Comparing the receptor affinity of the alkylated derivative with the receptor affinity of compounds possessing either ether or thioether groups revealed that conversion of the carbon atom to a sulfur atom did not influence the receptor affinity, whereas conversion to an oxygen atom was disadvantageous for the receptor affinity. The receptor affinity of compounds possessing a benzyl or phenyl group was lower than that of the unsubstituted compound. Analysis of the three-dimensional quantitative structure-activity relationship using comparative molecular field analysis demonstrated that steric hindrance of the receptor should exist around the C3 of an n-butyl group attached at position 5 on the imidazolidine ring. A docking study of the nAChR-ligand model suggested that the ligand-binding region expands as the length of the substituent increases by brushing against the amino acids that form the binding region. The insecticidal activity of the compounds was positively correlated with the receptor affinity by considering logP and the number of heteroatoms, including sulfur and oxygen atoms, in the substituents, suggesting that the insecticidal activity is influenced by the receptor affinity, hydrophobicity, and metabolic stability of the compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

Correlation between morphology, electron band structure, and resistivity of Pb atomic chains on the Si(5 5 3)-Au surface

NASA Astrophysics Data System (ADS)

Jałochowski, M.; Kwapiński, T.; Łukasik, P.; Nita, P.; Kopciuszyński, M.

2016-07-01

Structural and electron transport properties of multiple Pb atomic chains fabricated on the Si(5 5 3)-Au surface are investigated using scanning tunneling spectroscopy, reflection high electron energy diffraction, angular resolved photoemission electron spectroscopy and in situ electrical resistance. The study shows that Pb atomic chains growth modulates the electron band structure of pristine Si(5 5 3)-Au surface and hence changes its sheet resistivity. Strong correlation between chains morphology, electron band structure and electron transport properties is found. To explain experimental findings a theoretical tight-binding model of multiple atomic chains interacting on effective substrate is proposed.

Reverse engineering of an affinity-switchable molecular interaction characterized by atomic force microscopy single-molecule force spectroscopy.

PubMed

Anselmetti, Dario; Bartels, Frank Wilco; Becker, Anke; Decker, Björn; Eckel, Rainer; McIntosh, Matthew; Mattay, Jochen; Plattner, Patrik; Ros, Robert; Schäfer, Christian; Sewald, Norbert

2008-02-19

Tunable and switchable interaction between molecules is a key for regulation and control of cellular processes. The translation of the underlying physicochemical principles to synthetic and switchable functional entities and molecules that can mimic the corresponding molecular functions is called reverse molecular engineering. We quantitatively investigated autoinducer-regulated DNA-protein interaction in bacterial gene regulation processes with single atomic force microscopy (AFM) molecule force spectroscopy in vitro, and developed an artificial bistable molecular host-guest system that can be controlled and regulated by external signals (UV light exposure and thermal energy). The intermolecular binding functionality (affinity) and its reproducible and reversible switching has been proven by AFM force spectroscopy at the single-molecule level. This affinity-tunable optomechanical switch will allow novel applications with respect to molecular manipulation, nanoscale rewritable molecular memories, and/or artificial ion channels, which will serve for the controlled transport and release of ions and neutral compounds in the future.

Modeling the interaction of seven bisphosphonates with the hydroxyapatite(100) face.

PubMed

Chen, Chunyu; Xia, Mingzhu; Wu, Lei; Zhou, Chao; Wang, Fengyun

2012-09-01

The interaction of seven pamidronate bisphosphonate (Pami-BPs) and its analogs with the hydroxyapatite (HAP) (100) surface was studied using density functional theory (DFT) and molecular dynamic (MD) methods. Partial Mulliken oxygen atomic charges in protonated structures were calculated at the level of B3LYP/6-31G*. The MD simulation was performed using the Discover module of Material Studio by compass force field. The results indicate the abilities of donating electrons of the oxygen atoms of the phosphate groups that are closely associated with the antiresorptive potency. The binding energies, including vdw and electrostatic, are used to discuss the mechanism of antiresorption. The results of calculations show that the strength of interaction of the HAP (100) face with the bisphosphonates is N(4) > N(6) > N(7) > N(5) > N(3) > N(2) > N(1) according to their experimental pIC(50) values.

Watching proteins function with picosecond X-ray crystallography and molecular dynamics simulations.

NASA Astrophysics Data System (ADS)

Anfinrud, Philip

2006-03-01

Time-resolved electron density maps of myoglobin, a ligand-binding heme protein, have been stitched together into movies that unveil with < 2-å spatial resolution and 150-ps time-resolution the correlated protein motions that accompany and/or mediate ligand migration within the hydrophobic interior of a protein. A joint analysis of all-atom molecular dynamics (MD) calculations and picosecond time-resolved X-ray structures provides single-molecule insights into mechanisms of protein function. Ensemble-averaged MD simulations of the L29F mutant of myoglobin following ligand dissociation reproduce the direction, amplitude, and timescales of crystallographically-determined structural changes. This close agreement with experiments at comparable resolution in space and time validates the individual MD trajectories, which identify and structurally characterize a conformational switch that directs dissociated ligands to one of two nearby protein cavities. This unique combination of simulation and experiment unveils functional protein motions and illustrates at an atomic level relationships among protein structure, dynamics, and function. In collaboration with Friedrich Schotte and Gerhard Hummer, NIH.

G protein-coupled odorant receptors: From sequence to structure.

PubMed

de March, Claire A; Kim, Soo-Kyung; Antonczak, Serge; Goddard, William A; Golebiowski, Jérôme

2015-09-01

Odorant receptors (ORs) are the largest subfamily within class A G protein-coupled receptors (GPCRs). No experimental structural data of any OR is available to date and atomic-level insights are likely to be obtained by means of molecular modeling. In this article, we critically align sequences of ORs with those GPCRs for which a structure is available. Here, an alignment consistent with available site-directed mutagenesis data on various ORs is proposed. Using this alignment, the choice of the template is deemed rather minor for identifying residues that constitute the wall of the binding cavity or those involved in G protein recognition. © 2015 The Protein Society.

Doping Induced Structural Stability and Electronic Properties of GaN Nanotubes

PubMed Central

Khan, Mohammad Irfan; Tyagi, Neha; Swaroop Khare, Purnima

2014-01-01

The present paper discusses the effect of manganese doping on the structural stability and electronic band gap of chiral (2, 1), armchair (3, 3), and zigzag ((6, 0) and (10, 0)) single walled GaN nanotube by using density functional theory based Atomistix Toolkit (ATK) Virtual NanoLab (VNL). The structural stability has been analyzed in terms of minimum ground state total energy, binding, and formation energy. As an effect of Mn doping (1–4 atoms), all the GaN nanotubes taken into consideration show semiconducting to metallic transition first and after certain level of Mn doping changes its trend. PMID:24707225

Mg co-ordination with potential carcinogenic molecule acrylamide: Spectroscopic, computational and cytotoxicity studies

NASA Astrophysics Data System (ADS)

Singh, Ranjana; Mishra, Vijay K.; Singh, Hemant K.; Sharma, Gunjan; Koch, Biplob; Singh, Bachcha; Singh, Ranjan K.

2018-03-01

Acrylamide (acr) is a potential toxic molecule produced in thermally processed food stuff. Acr-Mg complex has been synthesized chemically and characterized by spectroscopic techniques. The binding sites of acr with Mg were identified by experimental and computational methods. Both experimental and theoretical results suggest that Mg coordinated with the oxygen atom of Cdbnd O group of acr. In-vitro cytotoxicity studies revealed significant decrease in the toxic level of acr-Mg complex as compared to pure acr. The decrease in toxicity on complexation with Mg may be a useful step for future research to reduce the toxicity of acr.

G protein-coupled odorant receptors: From sequence to structure

PubMed Central

de March, Claire A; Kim, Soo-Kyung; Antonczak, Serge; Goddard, William A; Golebiowski, Jérôme

2015-01-01

Odorant receptors (ORs) are the largest subfamily within class A G protein-coupled receptors (GPCRs). No experimental structural data of any OR is available to date and atomic-level insights are likely to be obtained by means of molecular modeling. In this article, we critically align sequences of ORs with those GPCRs for which a structure is available. Here, an alignment consistent with available site-directed mutagenesis data on various ORs is proposed. Using this alignment, the choice of the template is deemed rather minor for identifying residues that constitute the wall of the binding cavity or those involved in G protein recognition. PMID:26044705

Anti-inflammatory drugs interacting with Zn (II) metal ion based on thiocyanate and azide ligands: synthesis, spectroscopic studies, DFT calculations and antibacterial assays.

PubMed

Chiniforoshan, Hossein; Tabrizi, Leila; Hadizade, Morteza; Sabzalian, Mohammad R; Chermahini, Alireza Najafi; Rezapour, Mehdi

2014-07-15

Zinc (II) complexes with non-steroidal anti-inflammatory drugs (NSAIDs) naproxen (nap) and ibuprofen (ibu) were synthesized in the presence of nitrogen donor ligands (thiocyanate or azide). The complexes were characterized by elemental analysis, FT-IR, (1)H NMR and UV-Vis spectroscopes. The binding modes of the ligands in complexes were established by means of molecular modeling of the complexes, and calculation of their IR, NMR and absorption spectra at DFT (TDDFT)/B3LYP level were studied. The experimental and calculated data verified monodentate binding through the carboxylic oxygen atoms of anti-inflammatory drugs in the zinc complexes. The calculated (1)H, FT-IR and UV-Vis data are in better agreement with the experimental results, and confirm the predicted tetrahedral structures for the Zn (II) complexes. In addition to DFT calculations of complexes, natural bond orbital (NBO) was performed at B3LYP/6-31+G(d,p) level of theory. Biological studies showed the antibacterial activity of zinc complexes against Gram-positive and Gram-negative bacterial strains. Copyright © 2014 Elsevier B.V. All rights reserved.

Effect of inclusion of hydroxycinnamic and chlorogenic acids from green coffee bean in β-cyclodextrin on their interactions with whey, egg white and soy protein isolates.

PubMed

Budryn, Grażyna; Pałecz, Bartłomiej; Rachwał-Rosiak, Danuta; Oracz, Joanna; Zaczyńska, Donata; Belica, Sylwia; Navarro-González, Inmaculada; Meseguer, Josefina María Vegara; Pérez-Sánchez, Horacio

2015-02-01

The aim of the study was to characterise the interactions of hydroxycinnamic and chlorogenic acids (CHAs) from green coffee, with isolates of proteins from egg white (EWP), whey (WPC) and soy (SPI), depending on pH and temperature. The binding degree was determined by liquid chromatography coupled to a diode array detector and an ultrahigh resolution hybrid quadruple-time-of-flight mass spectrometer with ESI source (LC-QTOF-MS/MS). As a result of binding, the concentration of CHAs in proteins ranged from 9.44-12.2, 11.8-13.1 and 12.1-14.4g/100g for SPI, WPC and EWP, respectively. Thermodynamic parameters of protein-ligand interactions were determined by isothermal titration calorimetry (ITC) and energetics of interactions at the atomic level by molecular modelling. The amount of CHAs released during proteolytic digestion was in the range 0.33-2.67g/100g. Inclusion of CHAs with β-cyclodextrin strongly limited these interactions to a level of 0.03-0.06g/100g. Copyright © 2014 Elsevier Ltd. All rights reserved.

The binding of platinum hexahalides (Cl, Br and I) to hen egg-white lysozyme and the chemical transformation of the PtI{sub 6} octahedral complex to a PtI{sub 3} moiety bound to His15

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tanley, Simon W. M.; Starkey, Laurina-Victoria; Lamplough, Lucinda

The platinum hexahalides have an octahedral arrangement of six halogen atoms bound to a Pt centre, thus having an octahedral shape that could prove to be useful in interpreting poor electron-density maps. In a detailed characterization, PtI{sub 6} chemically transformed to a square-planar PtI{sub 3} complex bound to the N{sup δ} atom of His15 of HEWL was also observed, which was not observed for PtBr{sub 6} or PtCl{sub 6}. This study examines the binding and chemical stability of the platinum hexahalides K{sub 2}PtCl{sub 6}, K{sub 2}PtBr{sub 6} and K{sub 2}PtI{sub 6} when soaked into pre-grown hen egg-white lysozyme (HEWL) crystalsmore » as the protein host. Direct comparison of the iodo complex with the chloro and bromo complexes shows that the iodo complex is partly chemically transformed to a square-planar PtI{sub 3} complex bound to the N{sup δ} atom of His15, a chemical behaviour that is not exhibited by the chloro or bromo complexes. Each complex does, however, bind to HEWL in its octahedral form either at one site (PtI{sub 6}) or at two sites (PtBr{sub 6} and PtCl{sub 6}). As heavy-atom derivatives of a protein, the octahedral shape of the hexahalides could be helpful in cases of difficult-to-interpret electron-density maps as they would be recognisable ‘objects’.« less

Ultra-fast computation of electronic spectra for large systems by tight-binding based simplified Tamm-Dancoff approximation (sTDA-xTB)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grimme, Stefan, E-mail: grimme@thch.uni-bonn.de; Bannwarth, Christoph

2016-08-07

The computational bottleneck of the extremely fast simplified Tamm-Dancoff approximated (sTDA) time-dependent density functional theory procedure [S. Grimme, J. Chem. Phys. 138, 244104 (2013)] for the computation of electronic spectra for large systems is the determination of the ground state Kohn-Sham orbitals and eigenvalues. This limits such treatments to single structures with a few hundred atoms and hence, e.g., sampling along molecular dynamics trajectories for flexible systems or the calculation of chromophore aggregates is often not possible. The aim of this work is to solve this problem by a specifically designed semi-empirical tight binding (TB) procedure similar to the wellmore » established self-consistent-charge density functional TB scheme. The new special purpose method provides orbitals and orbital energies of hybrid density functional character for a subsequent and basically unmodified sTDA procedure. Compared to many previous semi-empirical excited state methods, an advantage of the ansatz is that a general eigenvalue problem in a non-orthogonal, extended atomic orbital basis is solved and therefore correct occupied/virtual orbital energy splittings as well as Rydberg levels are obtained. A key idea for the success of the new model is that the determination of atomic charges (describing an effective electron-electron interaction) and the one-particle spectrum is decoupled and treated by two differently parametrized Hamiltonians/basis sets. The three-diagonalization-step composite procedure can routinely compute broad range electronic spectra (0-8 eV) within minutes of computation time for systems composed of 500-1000 atoms with an accuracy typical of standard time-dependent density functional theory (0.3-0.5 eV average error). An easily extendable parametrization based on coupled-cluster and density functional computed reference data for the elements H–Zn including transition metals is described. The accuracy of the method termed sTDA-xTB is first benchmarked for vertical excitation energies of open- and closed-shell systems in comparison to other semi-empirical methods and applied to exemplary problems in electronic spectroscopy. As side products of the development, a robust and efficient valence electron TB method for the accurate determination of atomic charges as well as a more accurate calculation scheme of dipole rotatory strengths within the Tamm-Dancoff approximation is proposed.« less

2,3-Di(2-pyridyl)-5-phenylpyrazine: a NN-CNN-type bridging ligand for dinuclear transition-metal complexes.

PubMed

Wu, Si-Hai; Zhong, Yu-Wu; Yao, Jiannian

2013-07-01

A new bridging ligand, 2,3-di(2-pyridyl)-5-phenylpyrazine (dpppzH), has been synthesized. This ligand was designed so that it could bind two metals through a NN-CNN-type coordination mode. The reaction of dpppzH with cis-[(bpy)2RuCl2] (bpy = 2,2'-bipyridine) affords monoruthenium complex [(bpy)2Ru(dpppzH)](2+) (1(2+)) in 64 % yield, in which dpppzH behaves as a NN bidentate ligand. The asymmetric biruthenium complex [(bpy)2Ru(dpppz)Ru(Mebip)](3+) (2(3+)) was prepared from complex 1(2+) and [(Mebip)RuCl3] (Mebip = bis(N-methylbenzimidazolyl)pyridine), in which one hydrogen atom on the phenyl ring of dpppzH is lost and the bridging ligand binds to the second ruthenium atom in a CNN tridentate fashion. In addition, the RuPt heterobimetallic complex [(bpy)2Ru(dpppz)Pt(C≡CPh)](2+) (4(2+)) has been prepared from complex 1(2+), in which the bridging ligand binds to the platinum atom through a CNN binding mode. The electronic properties of these complexes have been probed by using electrochemical and spectroscopic techniques and studied by theoretical calculations. Complex 1(2+) is emissive at room temperature, with an emission λmax = 695 nm. No emission was detected for complex 2(3+) at room temperature in MeCN, whereas complex 4(2+) displayed an emission at about 750 nm. The emission properties of these complexes are compared to those of previously reported Ru and RuPt bimetallic complexes with a related ligand, 2,3-di(2-pyridyl)-5,6-diphenylpyrazine. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Density Functional Theory Investigation of Nin , Pdn , and Ptn Clusters (n=1-4) Adsorbed on Buckminsterfullerene.

PubMed

Pham, Nguyet N T; Le, Hung M

2017-05-19

In this study, we examine the adsorptions of Ni, Pd, and Pt clusters on C 60 by using a computational approach. Our calculation results show that the base structure of C 60 can host Ni n /Pd n /Pt n (n=1-4) clusters with good adsorption stability and the complexes establish either two or no unpaired electrons. The binding energy of Pd and Pt clusters increases as the number of metal atoms increases, implying that the coverage of C 60 with Pd or Pt preferentially establishes a large-size metal cluster. A single metal atom favorably occupies the C-C bridge site. For dimer clusters, the three metals of interest share a similar binding fashion, in which two metal atoms establish direct interactions with the C-C bridge sites. For trimer adsorptions, the formation of linear and triangular structures is observed. Both Pt 3 and Ni 3 preferably constitute isosceles triangles on C 60 , whilst Pd 3 favorably establishes a linear shape. Finally, for each of the Ni 4 and Pd 4 adsorption cases, we observed three stable binding configurations: rhombus, tetrahedron, and Y-form. Whereas Ni 4 establishes a tetrahedral form, Pd 4 attains the most stable form with the Y-shape geometry on C 60 . Overall, we observe that the trend of Pd binding to C 60 tends to go beyond the fashion of Ni and Pt. In terms of magnetic alignment, the Pd n -C 60 systems seem to be non-magnetic in most cases, unlike the Ni and Pt cases, the structures of which possess magnetic moments of 2 μB in their most stable forms. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Experimental and theoretical investigation of topological and energetic characteristics of Sb complexes reversibly binding molecular oxygen.

PubMed

Fukin, Georgy K; Baranov, Evgenii V; Jelsch, Christian; Guillot, Benoît; Poddel'sky, Andrey I; Cherkasov, Vladimir K; Abakumov, Gleb A

2011-07-28

The experimental distribution of electron density in Ph(3)(4,5-OMe-3,6-Bu(t)-Cat)Sb·MeCN (1*) and Ph(3)(4,5-N(2)C(4)H(6)-3,6-Bu(t)-Cat)Sb·MeOH (2*) complexes was studied. According to atoms in molecules theory, the Sb-C(Ph), Sb-O(catecholate), and Sb···N(O) bonds are intermediate, whereas the O-C and C-C bonds are covalent, respectively. The energy of the Sb···N(MeCN) and Sb···O(MeOH) bonds are 7.0 and 11.3 kcal/mol according to the Espinosa equation. Density functional theory and Hartree-Fock calculations were carried out for a series of catecholate and amidophenolate complexes of antimony(V). It was shown that such calculations reliably reproduce geometrical and topological parameters and therefore can be used for a criterion search of dioxygen reversible binding by the catecholate and amidophenolate complexes of antimony(V). It was found that the "critical" value of the HOMO energy vary in the range from -5.197 to -5.061 eV for reversible binding of dioxygen complexes. This can serve as a thermodynamic criterion to predict the possibility of the dioxygen reversible binding by the catecholate and amidophenolate complexes of Sb(V). The HOMO energies correlate with the conversion of the catecholate and amidophenolate complexes in corresponding spiroendoperoxide derivatives as well. The contribution of the atom orbitals of the carbon atoms in the five-membered metallocycle to HOMO in complexes with different substitutes in the 4- and 5-positions of the catecholate ligand allows predicting the place of dioxygen addition. © 2011 American Chemical Society

The structural, electronic and optical properties of Au-ZnO interface structure from the first-principles calculation

NASA Astrophysics Data System (ADS)

Huo, Jin-Rong; Li, Lu; Cheng, Hai-Xia; Wang, Xiao-Xu; Zhang, Guo-Hua; Qian, Ping

2018-03-01

The interface structure, electronic and optical properties of Au-ZnO are studied using the first-principles calculation based on density functional theory (DFT). Given the interfacial distance, bonding configurations and terminated surface, we built the optimal interface structure and calculated the electronic and optical properties of the interface. The total density of states, partial electronic density of states, electric charge density and atomic populations (Mulliken) are also displayed. The results show that the electrons converge at O atoms at the interface, leading to a stronger binding of interfaces and thereby affecting the optical properties of interface structures. In addition, we present the binding energies of different interface structures. When the interface structure of Au-ZnO gets changed, furthermore, varying optical properties are exhibited.

An affinity-structure database of helix-turn-helix: DNA complexes with a universal coordinate system.

PubMed

AlQuraishi, Mohammed; Tang, Shengdong; Xia, Xide

2015-11-19

Molecular interactions between proteins and DNA molecules underlie many cellular processes, including transcriptional regulation, chromosome replication, and nucleosome positioning. Computational analyses of protein-DNA interactions rely on experimental data characterizing known protein-DNA interactions structurally and biochemically. While many databases exist that contain either structural or biochemical data, few integrate these two data sources in a unified fashion. Such integration is becoming increasingly critical with the rapid growth of structural and biochemical data, and the emergence of algorithms that rely on the synthesis of multiple data types to derive computational models of molecular interactions. We have developed an integrated affinity-structure database in which the experimental and quantitative DNA binding affinities of helix-turn-helix proteins are mapped onto the crystal structures of the corresponding protein-DNA complexes. This database provides access to: (i) protein-DNA structures, (ii) quantitative summaries of protein-DNA binding affinities using position weight matrices, and (iii) raw experimental data of protein-DNA binding instances. Critically, this database establishes a correspondence between experimental structural data and quantitative binding affinity data at the single basepair level. Furthermore, we present a novel alignment algorithm that structurally aligns the protein-DNA complexes in the database and creates a unified residue-level coordinate system for comparing the physico-chemical environments at the interface between complexes. Using this unified coordinate system, we compute the statistics of atomic interactions at the protein-DNA interface of helix-turn-helix proteins. We provide an interactive website for visualization, querying, and analyzing this database, and a downloadable version to facilitate programmatic analysis. This database will facilitate the analysis of protein-DNA interactions and the development of programmatic computational methods that capitalize on integration of structural and biochemical datasets. The database can be accessed at http://ProteinDNA.hms.harvard.edu.

How soil organic matter composition controls hexachlorobenzene-soil-interactions: adsorption isotherms and quantum chemical modeling.

PubMed

Ahmed, Ashour A; Kühn, Oliver; Aziz, Saadullah G; Hilal, Rifaat H; Leinweber, Peter

2014-04-01

Hazardous persistent organic pollutants (POPs) interact in soil with the soil organic matter (SOM) but this interaction is insufficiently understood at the molecular level. We investigated the adsorption of hexachlorobenzene (HCB) on soil samples with systematically modified SOM. These samples included the original soil, the soil modified by adding a hot water extract (HWE) fraction (soil+3 HWE and soil+6 HWE), and the pyrolyzed soil. The SOM contents increased in the order pyrolyzed soil

Gamma Interferon-Induced Guanylate Binding Protein 1 Is a Novel Actin Cytoskeleton Remodeling Factor

PubMed Central

Ostler, Nicole; Britzen-Laurent, Nathalie; Liebl, Andrea; Naschberger, Elisabeth; Lochnit, Günter; Ostler, Markus; Forster, Florian; Kunzelmann, Peter; Ince, Semra; Supper, Verena; Praefcke, Gerrit J. K.; Schubert, Dirk W.; Stockinger, Hannes; Herrmann, Christian

2014-01-01

Gamma interferon (IFN-γ) regulates immune defenses against viruses, intracellular pathogens, and tumors by modulating cell proliferation, migration, invasion, and vesicle trafficking processes. The large GTPase guanylate binding protein 1 (GBP-1) is among the cellular proteins that is the most abundantly induced by IFN-γ and mediates its cell biologic effects. As yet, the molecular mechanisms of action of GBP-1 remain unknown. Applying an interaction proteomics approach, we identified actin as a strong and specific binding partner of GBP-1. Furthermore, GBP-1 colocalized with actin at the subcellular level and was both necessary and sufficient for the extensive remodeling of the fibrous actin structure observed in IFN-γ-exposed cells. These effects were dependent on the oligomerization and the GTPase activity of GBP-1. Purified GBP-1 and actin bound to each other, and this interaction was sufficient to impair the formation of actin filaments in vitro, as demonstrated by atomic force microscopy, dynamic light scattering, and fluorescence-monitored polymerization. Cosedimentation and band shift analyses demonstrated that GBP-1 binds robustly to globular actin and slightly to filamentous actin. This indicated that GBP-1 may induce actin remodeling via globular actin sequestering and/or filament capping. These results establish GBP-1 as a novel member within the family of actin-remodeling proteins specifically mediating IFN-γ-dependent defense strategies. PMID:24190970

Gamma interferon-induced guanylate binding protein 1 is a novel actin cytoskeleton remodeling factor.

PubMed

Ostler, Nicole; Britzen-Laurent, Nathalie; Liebl, Andrea; Naschberger, Elisabeth; Lochnit, Günter; Ostler, Markus; Forster, Florian; Kunzelmann, Peter; Ince, Semra; Supper, Verena; Praefcke, Gerrit J K; Schubert, Dirk W; Stockinger, Hannes; Herrmann, Christian; Stürzl, Michael

2014-01-01

Gamma interferon (IFN-γ) regulates immune defenses against viruses, intracellular pathogens, and tumors by modulating cell proliferation, migration, invasion, and vesicle trafficking processes. The large GTPase guanylate binding protein 1 (GBP-1) is among the cellular proteins that is the most abundantly induced by IFN-γ and mediates its cell biologic effects. As yet, the molecular mechanisms of action of GBP-1 remain unknown. Applying an interaction proteomics approach, we identified actin as a strong and specific binding partner of GBP-1. Furthermore, GBP-1 colocalized with actin at the subcellular level and was both necessary and sufficient for the extensive remodeling of the fibrous actin structure observed in IFN-γ-exposed cells. These effects were dependent on the oligomerization and the GTPase activity of GBP-1. Purified GBP-1 and actin bound to each other, and this interaction was sufficient to impair the formation of actin filaments in vitro, as demonstrated by atomic force microscopy, dynamic light scattering, and fluorescence-monitored polymerization. Cosedimentation and band shift analyses demonstrated that GBP-1 binds robustly to globular actin and slightly to filamentous actin. This indicated that GBP-1 may induce actin remodeling via globular actin sequestering and/or filament capping. These results establish GBP-1 as a novel member within the family of actin-remodeling proteins specifically mediating IFN-γ-dependent defense strategies.

Synergy of two low-affinity NLSs determines the high avidity of influenza A virus nucleoprotein NP for human importin α isoforms.

PubMed

Wu, Wei; Sankhala, Rajeshwer S; Florio, Tyler J; Zhou, Lixin; Nguyen, Nhan L T; Lokareddy, Ravi K; Cingolani, Gino; Panté, Nelly

2017-09-12

The influenza A virus nucleoprotein (NP) is an essential multifunctional protein that encapsidates the viral genome and functions as an adapter between the virus and the host cell machinery. NPs from all strains of influenza A viruses contain two nuclear localization signals (NLSs): a well-studied monopartite NLS1 and a less-characterized NLS2, thought to be bipartite. Through site-directed mutagenesis and functional analysis, we found that NLS2 is also monopartite and is indispensable for viral infection. Atomic structures of importin α bound to two variants of NLS2 revealed NLS2 primarily binds the major-NLS binding site of importin α, unlike NLS1 that associates with the minor NLS-pocket. Though peptides corresponding to NLS1 and NLS2 bind weakly to importin α, the two NLSs synergize in the context of the full length NP to confer high avidity for importin α7, explaining why the virus efficiently replicates in the respiratory tract that exhibits high levels of this isoform. This study, the first to functionally characterize NLS2, demonstrates NLS2 plays an important and unexpected role in influenza A virus infection. We propose NLS1 and NLS2 form a bipartite NLS in trans, which ensures high avidity for importin α7 while preventing non-specific binding to viral RNA.

The Protein-DNA Interface database

PubMed Central

2010-01-01

The Protein-DNA Interface database (PDIdb) is a repository containing relevant structural information of Protein-DNA complexes solved by X-ray crystallography and available at the Protein Data Bank. The database includes a simple functional classification of the protein-DNA complexes that consists of three hierarchical levels: Class, Type and Subtype. This classification has been defined and manually curated by humans based on the information gathered from several sources that include PDB, PubMed, CATH, SCOP and COPS. The current version of the database contains only structures with resolution of 2.5 Å or higher, accounting for a total of 922 entries. The major aim of this database is to contribute to the understanding of the main rules that underlie the molecular recognition process between DNA and proteins. To this end, the database is focused on each specific atomic interface rather than on the separated binding partners. Therefore, each entry in this database consists of a single and independent protein-DNA interface. We hope that PDIdb will be useful to many researchers working in fields such as the prediction of transcription factor binding sites in DNA, the study of specificity determinants that mediate enzyme recognition events, engineering and design of new DNA binding proteins with distinct binding specificity and affinity, among others. Finally, due to its friendly and easy-to-use web interface, we hope that PDIdb will also serve educational and teaching purposes. PMID:20482798

The Protein-DNA Interface database.

PubMed

Norambuena, Tomás; Melo, Francisco

2010-05-18

The Protein-DNA Interface database (PDIdb) is a repository containing relevant structural information of Protein-DNA complexes solved by X-ray crystallography and available at the Protein Data Bank. The database includes a simple functional classification of the protein-DNA complexes that consists of three hierarchical levels: Class, Type and Subtype. This classification has been defined and manually curated by humans based on the information gathered from several sources that include PDB, PubMed, CATH, SCOP and COPS. The current version of the database contains only structures with resolution of 2.5 A or higher, accounting for a total of 922 entries. The major aim of this database is to contribute to the understanding of the main rules that underlie the molecular recognition process between DNA and proteins. To this end, the database is focused on each specific atomic interface rather than on the separated binding partners. Therefore, each entry in this database consists of a single and independent protein-DNA interface.We hope that PDIdb will be useful to many researchers working in fields such as the prediction of transcription factor binding sites in DNA, the study of specificity determinants that mediate enzyme recognition events, engineering and design of new DNA binding proteins with distinct binding specificity and affinity, among others. Finally, due to its friendly and easy-to-use web interface, we hope that PDIdb will also serve educational and teaching purposes.

Dispersion- and Exchange-Corrected Density Functional Theory for Sodium Ion Hydration.

PubMed

Soniat, Marielle; Rogers, David M; Rempe, Susan B

2015-07-14

A challenge in density functional theory is developing functionals that simultaneously describe intermolecular electron correlation and electron delocalization. Recent exchange-correlation functionals address those two issues by adding corrections important at long ranges: an atom-centered pairwise dispersion term to account for correlation and a modified long-range component of the electron exchange term to correct for delocalization. Here we investigate how those corrections influence the accuracy of binding free energy predictions for sodium-water clusters. We find that the dual-corrected ωB97X-D functional gives cluster binding energies closest to high-level ab initio methods (CCSD(T)). Binding energy decomposition shows that the ωB97X-D functional predicts the smallest ion-water (pairwise) interaction energy and larger multibody contributions for a four-water cluster than most other functionals - a trend consistent with CCSD(T) results. Also, ωB97X-D produces the smallest amounts of charge transfer and the least polarizable waters of the density functionals studied, which mimics the lower polarizability of CCSD. When compared with experimental binding free energies, however, the exchange-corrected CAM-B3LYP functional performs best (error <1 kcal/mol), possibly because of its parametrization to experimental formation enthalpies. For clusters containing more than four waters, "split-shell" coordination must be considered to obtain accurate free energies in comparison with experiment.

Binding of Capsaicin to the TRPV1 Ion Channel.

PubMed

Darré, Leonardo; Domene, Carmen

2015-12-07

Transient receptor potential (TRP) ion channels constitute a notable family of cation channels involved in the ability of an organisms to detect noxious mechanical, thermal, and chemical stimuli that give rise to the perception of pain, taste, and changes in temperature. One of the most experimentally studied agonist of TRP channels is capsaicin, which is responsible for the burning sensation produced when chili pepper is in contact with organic tissues. Thus, understanding how this molecule interacts and regulates TRP channels is essential to high impact pharmacological applications, particularly those related to pain treatment. The recent publication of a three-dimensional structure of the vanilloid receptor 1 (TRPV1) in the absence and presence of capsaicin from single particle electron cryomicroscopy experiments provides the opportunity to explore these questions at the atomic level. In the present work, molecular docking and unbiased and biased molecular dynamics simulations were employed to generate a structural model of the capsaicin-channel complex. In addition, the standard free energy of binding was estimated using alchemical transformations coupled with conformational, translational, and orientational restraints on the ligand. Key binding modes consistent with previous experimental data are identified, and subtle but essential dynamical features of the binding site are characterized. These observations shed some light into how TRPV1 interacts with capsaicin, and may help to refine design parameters for new TRPV1 antagonists, and potentially guide further developments of TRP channel modulators.

A computational study to identify the key residues of peroxisome proliferator-activated receptor gamma in the interactions with its antagonists.

PubMed

Sharifi, Tayebeh; Ghayeb, Yousef

2018-05-01

Peroxisome proliferator-activated receptors (PPARs) compose a family of nuclear receptors, PPARα, PPARβ, and PPARγ, which mediate the effects of lipidic ligands at the transcriptional level. Among these, the PPARγ has been known to regulate adipocyte differentiation, fatty acid storage and glucose metabolism, and is a target of antidiabetic drugs. In this work, the interactions between PPARγ and its six known antagonists were investigated using computational methods such as molecular docking, molecular dynamics (MD) simulations, and the hybrid quantum mechanics/molecular mechanics (QM/MM). The binding energies evaluated by molecular docking varied between -22.59 and -35.15 kJ mol - 1 . In addition, MD simulations were performed to investigate the binding modes and PPARγ conformational changes upon binding of antagonists. Analysis of the root-mean-square fluctuations (RMSF) of backbone atoms shows that H3 of PPARγ has a higher mobility in the absence of antagonists and moderate conformational changes were observed. The interaction energies between antagonists and each PPARγ residue involved in the interactions were studied by QM/MM calculations. These calculations reveal that antagonists with different structures show different interaction energies with the same residue of PPARγ. Therefore, it can be concluded that the key residues vary depending on the structure of the ligand, which binds to PPARγ.

Distinguishing multiple chemotaxis Y protein conformations with laser-polarized 129Xe NMR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lowery, Thomas J.; Doucleff, Michealeen; Ruiz, E. Janette

2005-02-01

The chemical shift of the {sup 129}Xe NMR signal has been shown to be extremely sensitive to the local environment around the atom and has been used to follow processes such as ligand binding by bacterial periplasmic binding proteins (Rubin et al. 2000; Lowery et al. 2004). Here we show that the {sup 129}Xe shift can sense more subtle changes: magnesium binding, BeF{sub 3}{sup -} activation, and peptide binding by the E. coli chemotaxis Y protein. {sup 1}H-{sup 15}N correlation spectroscopy and x-ray crystallography were used to identify two xenon-binding cavities in CheY that are primarily responsible for the shiftmore » changes. One site is near the active site, and the other is near the peptide binding site.« less

Modeling Linear and Cyclic PKS Intermediates through Atom Replacement

PubMed Central

2015-01-01

The mechanistic details of many polyketide synthases (PKSs) remain elusive due to the instability of transient intermediates that are not accessible via conventional methods. Here we report an atom replacement strategy that enables the rapid preparation of polyketone surrogates by selective atom replacement, thereby providing key substrate mimetics for detailed mechanistic evaluations. Polyketone mimetics are positioned on the actinorhodin acyl carrier protein (actACP) to probe the underpinnings of substrate association upon nascent chain elongation and processivity. Protein NMR is used to visualize substrate interaction with the actACP, where a tetraketide substrate is shown not to bind within the protein, while heptaketide and octaketide substrates show strong association between helix II and IV. To examine the later cyclization stages, we extended this strategy to prepare stabilized cyclic intermediates and evaluate their binding by the actACP. Elongated monocyclic mimics show much longer residence time within actACP than shortened analogs. Taken together, these observations suggest ACP-substrate association occurs both before and after ketoreductase action upon the fully elongated polyketone, indicating a key role played by the ACP within PKS timing and processivity. These atom replacement mimetics offer new tools to study protein and substrate interactions and are applicable to a wide variety of PKSs. PMID:25406716

Microsolvation effect and hydrogen-bonding pattern of taurine-water TA-(H2O)n (n = 1-3) complexes.

PubMed

Dai, Yumei; Wang, Yuhua; Huang, Zhengguo; Wang, Hongke; Yu, Lei

2012-01-01

The microsolvation of taurine (TA) with one, two or three water molecules was investigated by a density functional theory (DFT) approach. Quantum theory of atoms in molecules (QTAIM) analyses were employed to elucidate the hydrogen bond (H-bond) interaction characteristics in TA-(H(2)O)(n) (n = 1-3) complexes. The results showed that the intramolecular H-bond formed between the hydroxyl and the N atom of TA are retained in most TA-(H(2)O)(n) (n = 1-3) complexes, and are strengthened via cooperative effects among multiple H-bonds from n = 1-3. A trend of proton transformation exists from the hydroxyl to the N atom, which finally results in the cleavage of the origin intramolecular H-bond and the formation of a new intramolecular H-bond between the amino and the O atom of TA. Therefore, the most stable TA-(H(2)O)(3) complex becomes a zwitterionic complex rather than a neutral type. A many-body interaction analysis showed that the major contributors to the binding energies for complexes are the two-body energies, while three-body energies and relaxation energies make significant contributions to the binding energies for some complexes, whereas the four-body energies are too small to be significant.

Extension of the self-consistent-charge density-functional tight-binding method: third-order expansion of the density functional theory total energy and introduction of a modified effective coulomb interaction.

PubMed

Yang, Yang; Yu, Haibo; York, Darrin; Cui, Qiang; Elstner, Marcus

2007-10-25

The standard self-consistent-charge density-functional-tight-binding (SCC-DFTB) method (Phys. Rev. B 1998, 58, 7260) is derived by a second-order expansion of the density functional theory total energy expression, followed by an approximation of the charge density fluctuations by charge monopoles and an effective damped Coulomb interaction between the atomic net charges. The central assumptions behind this effective charge-charge interaction are the inverse relation of atomic size and chemical hardness and the use of a fixed chemical hardness parameter independent of the atomic charge state. While these approximations seem to be unproblematic for many covalently bound systems, they are quantitatively insufficient for hydrogen-bonding interactions and (anionic) molecules with localized net charges. Here, we present an extension of the SCC-DFTB method to incorporate third-order terms in the charge density fluctuations, leading to chemical hardness parameters that are dependent on the atomic charge state and a modification of the Coulomb scaling to improve the electrostatic treatment within the second-order terms. These modifications lead to a significant improvement in the description of hydrogen-bonding interactions and proton affinities of biologically relevant molecules.

Crystal structures of palladium(II) ternary complexes of 5-x-2-aminobenzoic acid with 1,10-phenanthroline and their interaction with calf thymus DNA (where X=Cl, Br and I).

PubMed

Wang, Yue; Okabe, Nobuo; Odoko, Mamiko

2005-10-01

The crystal structures of a series of three palladium(II) ternary complexes of 5-halogeno-2-aminobenzoic acid (5-X-AB, where X=Cl, Br and I) with 1,10-phenanthroline [Pd(5-Cl-AB)(phen)] (1), [Pd(5-Br-AB)(phen)] (2) and [Pd(5-I-AB)(phen)] (3) have been determined, and their coordination geometries and the crystal architecture characterized. All of the complexes are an isostructure in which each Pd(II) atom has basically similar square planar coordination geometry. The substitute halogen group at 5-position of AB plays an important role in producing the coordination bonds of the carboxylate and amino groups in which the carboxylate O atom and the amino N atom act as the negative monodentate ligand atoms. The coordination bond distances of O-Pd increase in the order 1<2<3, while those of N-Pd decrease in the same order. The binding of the complexes to the calf thymus DNA has also been studied by the fluorescence method. Each of the complexes shows high binding propensity to DNA which can be reflected as the relative order 1<2<3.

Adsorption of hydrogen on stable and metastable Ir(100) surfaces

NASA Astrophysics Data System (ADS)

Arman, Mohammad Alif; Klein, Andreas; Ferstl, Pascal; Valookaran, Abhilash; Gustafson, Johan; Schulte, Karina; Lundgren, Edvin; Heinz, Klaus; Schneider, Alexander; Mittendorfer, Florian; Hammer, Lutz; Knudsen, Jan

2017-02-01

Using the combination of high resolution core level spectroscopy and density functional theory we present a detailed spectroscopic study for all clean and hydrogen covered phases of Ir(100). The results are complemented by an investigation of the hydrogen desorption process from various phases using temperature programmed desorption spectroscopy and scanning tunneling microscopy. In total, all experimentally determined core level shifts match very well with those predicted by density functional theory based on established structural models. In particular, we find for the (bridge site) adsorption on the unreconstructed 1×1 phase that the initial core level shift of surface Ir atoms is altered by +0.17 eV for each Ir-H bond formed. In the submonolayer regime we find evidence for island formation at low temperatures. For the H-induced deconstructed 5×1-H phase we identify four different surface core level shifts with two of them being degenerate. Finally, for the reconstructed 5×1-hex phase also four surface components are identified, which undergo a rather rigid core level shift of +0.15 eV upon hydrogen adsorption suggesting a similarly homogeneous charge transfer to all Ir surface atoms. Thermodesorption experiments for the 5×1-H phase reveal two different binding states for hydrogen independent of the total coverage. We conclude that the surface always separates into patches of fully covered deconstructed and uncovered reconstructed phases. We could also show by tunneling microscopy that with the desorption of the last hydrogen atom from the deconstructed unit cell the surface instantaneously reverts into the reconstructed state. Eventually, we could determine the saturation coverage upon molecular adsorption for all phases to be θmax1 × 1 - H = 1.0 ML , θmax5 × 1 - H = 0.8 ML , and θmax5 × 1 - hex - H ≥ 1.0 ML .

Weak interactions and cooperativity effects on disiloxane: a look at the building block of silicones

NASA Astrophysics Data System (ADS)

Martín-Fernández, Carlos; Montero-Campillo, M. Merced; Alkorta, Ibon; Elguero, José

2018-06-01

The behaviour of disiloxane 1 towards a set of Lewis acids (LA) and Lewis bases (LB) forming complexes through its oxygen and silicon atoms, respectively, was studied at the MP2/aug‧-cc-pVTZ level of theory, exploring a wide variety of non-covalent interactions. Disiloxane is a moderate electron acceptor and a good electron donor, exhibiting in the latter case binding energies up to almost -100 kJ/mol with BeCl2. Cooperativity effects were also analysed by looking at ternary 1:LA:LB complexes. Shorter intermolecular distances than in the corresponding binary complexes and a negative contribution of the three-body term to the binding energy indicate that the non-covalent interactions allowed by disiloxane through its acid and basic centres cooperate between them to reinforce both donor-acceptor pairs. These effects are particularly strong in complexes involving beryllium and triel bonds, but are also relevant for complexes containing hydrogen bonds.

Three pillars for achieving quantum mechanical molecular dynamics simulations of huge systems: Divide-and-conquer, density-functional tight-binding, and massively parallel computation.

PubMed

Nishizawa, Hiroaki; Nishimura, Yoshifumi; Kobayashi, Masato; Irle, Stephan; Nakai, Hiromi

2016-08-05

The linear-scaling divide-and-conquer (DC) quantum chemical methodology is applied to the density-functional tight-binding (DFTB) theory to develop a massively parallel program that achieves on-the-fly molecular reaction dynamics simulations of huge systems from scratch. The functions to perform large scale geometry optimization and molecular dynamics with DC-DFTB potential energy surface are implemented to the program called DC-DFTB-K. A novel interpolation-based algorithm is developed for parallelizing the determination of the Fermi level in the DC method. The performance of the DC-DFTB-K program is assessed using a laboratory computer and the K computer. Numerical tests show the high efficiency of the DC-DFTB-K program, a single-point energy gradient calculation of a one-million-atom system is completed within 60 s using 7290 nodes of the K computer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Macrolide antibiotic interaction and resistance on the bacterial ribosome.

PubMed

Poehlsgaard, Jacob; Douthwaite, Stephen

2003-02-01

Our understanding of the fine structure of many antibiotic target sites has reached a new level of enlightenment in the last couple of years due to the advent, by X-ray crystallography, of high-resolution structures of the bacterial ribosome. Many classes of clinically useful antibiotics bind to the ribosome to inhibit bacterial protein synthesis. Macrolide, lincosamide and streptogramin B (MLSB) antibiotics form one of the largest groups, and bind to the same site on the 50S ribosomal subunit. Here, we review the molecular details of the ribosomal MLSB site to put into perspective the main points from a wealth of biochemical and genetic data that have been collected over several decades. The information is now available to understand, at atomic resolution, how macrolide antibiotics interact with their ribosomal target, how the target is altered to confer resistance, and in which directions we need to look if we are to rationally design better drugs to overcome the extant resistance mechanisms.

Iron ion and iron hydroxide adsorption to charge-neutral phosphatidylcholine templates

DOE PAGES

Wang, Wenjie; Zhang, Honghu; Feng, Shuren; ...

2016-07-13

Surface-sensitive X-ray scattering and spectroscopy techniques reveal significant adsorption of iron ions and iron-hydroxide (Fe(III)) complexes to a charge-neutral zwitterionic template of phosphatidylcholine (PC). The PC template is formed by a Langmuir monolayer of dipalmitoyl-PC (DPPC) that is spread on the surface of 2 to 40 μM FeCl 3 solutions at physiological levels of KCl (100 mM). At 40 μM of Fe(III) as many as ~3 iron atoms are associated with each PC group. Grazing incidence X-ray diffraction measurements indicate a significant disruption in the in-plane ordering of DPPC molecules upon iron adsorption. The binding of iron-hydroxide complexes to amore » neutral PC surface is yet another example of nonelectrostatic, presumably covalent bonding to a charge-neutral organic template. Furthermore, the strong binding and the disruption of in-plane lipid structure has biological implications on the integrity of PC-derived lipid membranes, including those based on sphingomyelin.« less

Observation of a shape resonance of the positronium negative ion

PubMed Central

Michishio, Koji; Kanai, Tsuneto; Kuma, Susumu; Azuma, Toshiyuki; Wada, Ken; Mochizuki, Izumi; Hyodo, Toshio; Yagishita, Akira; Nagashima, Yasuyuki

2016-01-01

When an electron binds to its anti-matter counterpart, the positron, it forms the exotic atom positronium (Ps). Ps can further bind to another electron to form the positronium negative ion, Ps− (e−e+e−). Since its constituents are solely point-like particles with the same mass, this system provides an excellent testing ground for the three-body problem in quantum mechanics. While theoretical works on its energy level and dynamics have been performed extensively, experimental investigations of its characteristics have been hampered by the weak ion yield and short annihilation lifetime. Here we report on the laser spectroscopy study of Ps−, using a source of efficiently produced ions, generated from the bombardment of slow positrons onto a Na-coated W surface. A strong shape resonance of 1Po symmetry has been observed near the Ps (n=2) formation threshold. The resonance energy and width measured are in good agreement with the result of three-body calculations. PMID:26983496

Structure of a Clostridium botulinum C143S thiaminase I/thiamin complex reveals active site architecture .

PubMed

Sikowitz, Megan D; Shome, Brateen; Zhang, Yang; Begley, Tadhg P; Ealick, Steven E

2013-11-05

Thiaminases are responsible for the degradation of thiamin and its metabolites. Two classes of thiaminases have been identified based on their three-dimensional structures and their requirements for a nucleophilic second substrate. Although the reactions of several thiaminases have been characterized, the physiological role of thiamin degradation is not fully understood. We have determined the three-dimensional X-ray structure of an inactive C143S mutant of Clostridium botulinum (Cb) thiaminase I with bound thiamin at 2.2 Å resolution. The C143S/thiamin complex provides atomic level details of the orientation of thiamin upon binding to Cb-thiaminase I and the identity of active site residues involved in substrate binding and catalysis. The specific roles of active site residues were probed by using site directed mutagenesis and kinetic analyses, leading to a detailed mechanism for Cb-thiaminase I. The structure of Cb-thiaminase I is also compared to the functionally similar but structurally distinct thiaminase II.

Thymol nanoencapsulated by sodium caseinate: physical and antilisterial properties.

PubMed

Pan, Kang; Chen, Huaiqiong; Davidson, P Michael; Zhong, Qixin

2014-02-19

In this work, thymol was encapsulated in sodium caseinate using high shear homogenization. The transparent dispersion at neutral pH was stable for 30 days at room temperature as determined by dynamic light scattering and atomic force microscopy, which agreed with high ζ potential of nanoparticles. The slightly decreased particle dimension during storage indicates the absence of Ostwald ripening. When molecular binding was studied by fluorescence spectroscopy, thymol was observed to bind with tyrosine and possibly other amino acid residues away from tryptophan of caseins. At pH 4.6 (isoelectric point of caseins), the stabilization of thymol nanoparticles against aggregation was enabled by soluble soybean polysaccharide, resulting from the combined electrostatic and steric repulsions. The encapsulated thymol showed the significantly improved antilisterial activity in milk with different fat levels when compared to thymol crystals, resulting from the quicker mixing and increased solubility in the milk serum. The transparent thymol nanodispersions have promising applications to improve microbiological safety and quality of foods.

QSAR modeling of β-lactam binding to human serum proteins

NASA Astrophysics Data System (ADS)

Hall, L. Mark; Hall, Lowell H.; Kier, Lemont B.

2003-02-01

The binding of beta-lactams to human serum proteins was modeled with topological descriptors of molecular structure. Experimental data was the concentration of protein-bound drug expressed as a percent of the total plasma concentration (percent fraction bound, PFB) for 87 penicillins and for 115 β-lactams. The electrotopological state indices (E-State) and the molecular connectivity chi indices were found to be the basis of two satisfactory models. A data set of 74 penicillins from a drug design series was successfully modeled with statistics: r2=0.80, s = 12.1, q2=0.76, spress=13.4. This model was then used to predict protein binding (PFB) for 13 commercial penicillins, resulting in a very good mean absolute error, MAE = 12.7 and correlation coefficient, q2=0.84. A group of 28 cephalosporins were combined with the penicillin data to create a dataset of 115 beta-lactams that was successfully modeled: r2=0.82, s = 12.7, q2=0.78, spress=13.7. A ten-fold 10% leave-group-out (LGO) cross-validation procedure was implemented, leading to very good statistics: MAE = 10.9, spress=14.0, q2 (or r2 press)=0.78. The models indicate a combination of general and specific structure features that are important for estimating protein binding in this class of antibiotics. For the β-lactams, significant factors that increase binding are presence and electron accessibility of aromatic rings, halogens, methylene groups, and =N- atoms. Significant negative influence on binding comes from amine groups and carbonyl oxygen atoms.

Computing the binding affinity of Zn2+ in human carbonic anhydrase II on the basis of all-atom molecular dynamics simulations.

NASA Astrophysics Data System (ADS)

Wambo, Thierry; Rodriguez, Roberto

Human carbonic anhydrase II (hCAII) is a metalloenzyme with a Zinc cation at its binding site. The presence of the Zinc turns the protein into an efficient enzyme which catalyzes the reversible hydration of carbon dioxide into bicarbonate anion. Available X-ray structures of the apo-hCAII and holo-hCAII show no significant differences in the overall structure of these proteins. What difference, if any, is there between the structures of the hydrated apo-hCAII and holo? How can we use computer simulation to efficiently compute the binding affinity of Zinc to hCAII? We will present a scheme developed to compute the binding affinity of Zinc cation to hCAII on the basis of all-atom molecular dynamics simulation where Zinc is represented as a point charge and the CHARMM36 force field is used for running the dynamics of the system. Our computed binding affinity of the cation to hCAII is in good agreement with experiment, within the margin of error, while a look at the dynamics of the binding site suggests that in the absence of the Zinc, there is a re-organization of the nearby histidine residues which adopt a new distinct configuration. The authors are thankful for the NIH support through Grants GM084834 and GM060655. They also acknowledge the Texas Advanced Computing Center at the University of Texas at Austin for the supercomputing time. They thank Dr Liao Chen for his comments.

Investigating the properties and interaction mechanism of nano-silica in polyvinyl alcohol/polyacrylamide blends at an atomic level.

PubMed

Wei, Qinghua; Wang, Yanen; Wang, Shuzhi; Zhang, Yingfeng; Chen, Xiongbiao

2017-11-01

The nano-silica can be incorporated into polymers for improved mechanical properties. Notably, the interaction between nano-silica and polymer is of a microscopic phenomenon and thus, hard to observe and study by using experimental methods. Based on molecular dynamics, this paper presents a study on the properties and the interaction mechanism of nano-silica in the polyvinyl alcohol (PVA)/polyacrylamide (PAM) blends at an atomic level. Specifically, six blends of PVA/PAM with varying concentrations of nano-silica (0-13wt%) and two interfacial interaction models of polymers on the silica surface were designed and analyzed at an atomic level in terms of concentration profile, mechanical properties, fractional free volume (FFV), dynamic properties of polymers and X-ray diffraction patterns. The concentration profile results and micromorphologies of equilibrium models suggest PAM molecular chains are easier to be adsorbed on the silica surface than PVA molecular chains in blends. The incorporation of nano-silica into the PVA/PAM blends can increase the blend mechanical properties, densities, and semicrystalline character. Meanwhile, the FFV and the mobility of polymer chain decrease with the silica concentration, which agrees with the results of mechanical properties, densities, and semicrystalline character. Our results also illustrate that an analysis of binding energies and pair correlation functions (PCF) allows for the discovery of the interaction mechanism of nano-silica in PVA/PAM blends; and that hydrogen bond interactions between polar functional groups of polymer molecular chains and the hydroxyl groups of the silica surface are involved in adsorption of the polymers on the silica surface, thus affecting the interaction mechanism of nano-silica in PVA/PAM blend systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect on magnetic properties of germanium encapsulated C60 fullerene

NASA Astrophysics Data System (ADS)

Umran, Nibras Mossa; Kumar, Ranjan

2013-02-01

Structural and electronic properties of Gen(n = 1-4) doped C60 fullerene are investigated with ab initio density functional theory calculations by using an efficient computer code, known as SIESTA. The pseudopotentials are constructed using a Trouiller-Martins scheme, to describe the interaction of valence electrons with the atomic cores. In endohedral doped embedding of more germanium atoms complexes we have seen that complexes are stable and thereafter cage break down. We have also investigated that binding energy, electronic affinity increases and magnetic moment oscillating behavior as the number of semiconductor atoms in C60 fullerene goes on increasing.

The mechanism of water/ion exchange at a protein surface: a weakly bound chloride in Helicobacter pylori apoflavodoxin.

PubMed

Galano-Frutos, Juan J; Morón, M Carmen; Sancho, Javier

2015-11-21

Binding/unbinding of small ligands, such as ions, to/from proteins influences biochemical processes such as protein folding, enzyme catalysis or protein/ligand recognition. We have investigated the mechanism of chloride/water exchange at a protein surface (that of the apoflavodoxin from Helicobacter pylori) using classical all-atom molecular dynamics simulations. They reveal a variety of chloride exit routes and residence times; the latter is related to specific coordination modes of the anion. The role of solvent molecules in the mechanism of chloride unbinding has been studied in detail. We see no temporary increase in chloride coordination along the release process. Instead, the coordination of new water molecules takes place in most cases after the chloride/protein atom release event has begun. Moreover, the distribution function of water entrance events into the first chloride solvation shell peaks after chloride protein atom dissociation events. All these observations together seem to indicate that water molecules simply fill the vacancies left by the previously coordinating protein residues. We thus propose a step-by-step dissociation pathway in which protein/chloride interactions gradually break down before new water molecules progressively fill the vacant positions left by protein atoms. As observed for other systems, water molecules associated with bound chloride or with protein atoms have longer residence times than those bound to the free anion. The implications of the exchange mechanism proposed for the binding of the FMN (Flavin Mononucleotide) protein cofactor are discussed.

Nonextensive Thomas-Fermi model

NASA Astrophysics Data System (ADS)

Shivamoggi, Bhimsen; Martinenko, Evgeny

2007-11-01

Nonextensive Thomas-Fermi model was father investigated in the following directions: Heavy atom in strong magnetic field. following Shivamoggi work on the extension of Kadomtsev equation we applied nonextensive formalism to father generalize TF model for the very strong magnetic fields (of order 10e12 G). The generalized TF equation and the binding energy of atom were calculated which contain a new nonextensive term dominating the classical one. The binding energy of a heavy atom was also evaluated. Thomas-Fermi equations in N dimensions which is technically the same as in Shivamoggi (1998) ,but behavior is different and in interesting 2 D case nonextesivity prevents from becoming linear ODE as in classical case. Effect of nonextensivity on dielectrical screening reveals itself in the reduction of the envelope radius. It was shown that nonextesivity in each case is responsible for new term dominating classical thermal correction term by order of magnitude, which is vanishing in a limit q->1. Therefore it appears that nonextensive term is ubiquitous for a wide range of systems and father work is needed to understand the origin of it.

A DFT study for the structural and electronic properties of Zn m Se n nanoclusters

NASA Astrophysics Data System (ADS)

Yadav, Phool Singh; Pandey, Dheeraj Kumar

2012-09-01

An ab initio study has been performed for the stability, structural and electronic properties of 19 small zinc selenide Zn m Se n ( m + n = 2-4) nanoclusters. Out of these nanoclusters, one nanocluster is found to be unstable due to its imaginary vibrational frequency. A B3LYP-DFT/6-311G(3df) method is used in the optimization of the geometries of the nanoclusters. We have calculated the zero point energy (ZPE), which is ignored by the other workers. The binding energies (BE), HOMO-LUMO gaps and bond lengths have been obtained for all the optimized nanoclusters. For the same value of ` m' and ` n', we designate the most stable structure the one, which has maximum final binding energy (FBE) per atom. The adiabatic and vertical ionization potentials (IP) and electron affinities (EA), dipole moments and charge on atoms have been investigated for the most stable nanoclusters. For the same value of ` m' and ` n', the nanocluster containing maximum number of Se atoms is found to be most stable.

Linker Dependent Bond Rupture Force Measurements in Single-Molecule Junctions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frei M.; Hybertsen M.; Aradhya S.V.

We use a modified conducting atomic force microscope to simultaneously probe the conductance of a single-molecule junction and the force required to rupture the junction formed by alkanes terminated with four different chemical link groups which vary in binding strength and mechanism to the gold electrodes. Molecular junctions with amine, methylsulfide, and diphenylphosphine terminated molecules show clear conductance signatures and rupture at a force that is significantly smaller than the measured 1.4 nN force required to rupture the single-atomic gold contact. In contrast, measurements with a thiol terminated alkane which can bind covalently to the gold electrode show conductance andmore » force features unlike those of the other molecules studied. Specifically, the strong Au-S bond can cause structural rearrangements in the electrodes, which are accompanied by substantial conductance changes. Despite the strong Au-S bond and the evidence for disruption of the Au structure, the experiments show that on average these junctions also rupture at a smaller force than that measured for pristine single-atom gold contacts.« less

Studies of the Interaction of Influenza Virus RNA Polymerase PAN with Endonuclease Inhibitors.

PubMed

Dong, Li-Hua; Cao, Xiao-Rong

2018-06-01

Influenza virus is a major causative agent of respiratory viral infections, and RNA polymerase catalyzes its replication and transcription activities in infected cell nuclei. Since it is highly conserved in all virus strains, RNA polymerase becomes a key target of anti-influenza virus agents. Although experimental studies have revealed the good inhibitory activity of endonuclease inhibitors to RNA polymerase, the mechanism is still unclear. In this study, the docking and molecular dynamics simulations have been performed to explore the interaction of three kinds of endonuclease inhibitors with the subunit (PA N ) of RNA polymerase. Our calculations indicate that all these endonuclease inhibitors can bind to the binding pocket of PA N , in which the electronegative oxygen atoms of the inhibitors form a chelated structure with the two Mn 2+ cations of the active center. The most important interaction between these inhibitors and PA N is electrostatic interaction. The electron density of the chelate oxygen atoms determines the magnitude of the electrostatic energy, and the chelated structure and orientation of inhibitors depend largely on the distance between the chelate oxygen atoms.

Expression, purification and crystallization of a human protein SH3BGRL at atomic resolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yin, Lei; Zhu, De-Yu; Yang, Na

2005-04-01

The protein SH3BGRL, containing both SH3-binding and Homer EVH1-binding motifs, has been crystallized using the hanging-drop vapour-diffusion method. The protein SH3BGRL, containing both SH3-binding and Homer EVH1-binding motifs, has been crystallized using the hanging-drop vapour-diffusion method. The crystals diffract to 0.88 Å resolution and belong to space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 28.8886, b = 34.9676, c = 98.0016 Å. Preliminary analysis indicates that the asymmetric unit contains one molecule and has a solvent content of about 34%.

Modelling realistic TiO2 nanospheres: A benchmark study of SCC-DFTB against hybrid DFT

NASA Astrophysics Data System (ADS)

Selli, Daniele; Fazio, Gianluca; Di Valentin, Cristiana

2017-10-01

TiO2 nanoparticles (NPs) are nowadays considered fundamental building blocks for many technological applications. Morphology is found to play a key role with spherical NPs presenting higher binding properties and chemical activity. From the experimental point of view, the characterization of these nano-objects is extremely complex, opening a large room for computational investigations. In this work, TiO2 spherical NPs of different sizes (from 300 to 4000 atoms) have been studied with a two-scale computational approach. Global optimization to obtain stable and equilibrated nanospheres was performed with a self-consistent charge density functional tight-binding (SCC-DFTB) simulated annealing process, causing a considerable atomic rearrangement within the nanospheres. Those SCC-DFTB relaxed structures have been then optimized at the DFT(B3LYP) level of theory. We present a systematic and comparative SCC-DFTB vs DFT(B3LYP) study of the structural properties, with particular emphasis on the surface-to-bulk sites ratio, coordination distribution of surface sites, and surface energy. From the electronic point of view, we compare HOMO-LUMO and Kohn-Sham gaps, total and projected density of states. Overall, the comparisons between DFTB and hybrid density functional theory show that DFTB provides a rather accurate geometrical and electronic description of these nanospheres of realistic size (up to a diameter of 4.4 nm) at an extremely reduced computational cost. This opens for new challenges in simulations of very large systems and more extended molecular dynamics.

Adenylosuccinate synthetase: recent developments.

PubMed

Honzatko, R B; Stayton, M M; Fromm, H J

1999-01-01

By exerting strategic control on purine nucleotide biosynthesis, and by engaging GTP-dependent transphosphorylation of IMP to activate loss of an oxygen atom during catalysis, adenylosuccinate synthetase remains as enzyme that justifiably fascinates students of enzyme catalysis. This review describes how the balanced application of X-ray crystallography and enzyme kinetics has advanced the comprehension of the catalytic and regulatory properties of adenylosuccinate synthetase. Detailed analysis has demonstrated the formation of 6-phosphoryl-IMP, an intermediate originally postulated over 40 years ago on the basis of oxygen-18 exchange experiments showing that position-6 oxygen of IMP becomes incorporated into phosphate. Inferences about the participation of amino acid side-chains that stabilize 6-P-IMP during catalysis have also been confirmed by site-directed mutagenesis and examination of such mutations on various kinetic parameters. Moreover, the action of certain regulatory ligands have also been viewed at atomic level resolution. For example, magnesium ion and GDP can induce conformational changes linked to the stabilization of one of two known conformations of the so-called 40s loop. Another significant finding is that two magnesium ions play fundamental roles: one binding with high affinity to the substrate GTP, and a second binding with lower affinity to the co-substrate aspartate. These structural and kinetic studies have also formed the basis for clarifying the action of various inhibitors and potentially important pharmacologic agents with this key regulatory enzyme. Finally, this review explores the current status of investigations on gene structure and gene expression in a number of organisms.

Interaction analysis of chimeric metal-binding green fluorescent protein and artificial solid-supported lipid membrane by quartz crystal microbalance and atomic force microscopy.

PubMed

Prachayasittikul, Virapong; Isarankura Na Ayudhya, Chartchalerm; Hilterhaus, Lutz; Hinz, Andreas; Tantimongcolwat, Tanawut; Galla, Hans-Joachim

2005-02-04

Non-specific adsorption and specific interaction between a chimeric green fluorescent protein (GFP) carrying metal-binding region and the immobilized zinc ions on artificial solid-supported lipid membranes was investigated using the quartz crystal microbalance technique and the atomic force microscopy (AFM). Supported lipid bilayer, composed of octanethiol and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycero-3-[N-(5-amino-1-carboxypentyl iminodiacetic acid)succinyl] (NTA-DOGS)-Zn2+, was formed on the gold electrode of quartz resonator (5 MHz). Binding of the chimeric GFP to zinc ions resulted in a rapid decrease of resonance frequency. Reversibility of the process was demonstrated via the removal of metal ions by EDTA. Nanoscale structural orientation of the chimeric GFP on the membrane was imaged by AFM. Association constant of the specific binding to metal ions was 2- to 3-fold higher than that of the non-specific adsorption, which was caused by the fluidization effect of the metal-chelating lipid molecules as well as the steric hindrance effect. This infers a possibility for a further development of biofunctionalized membrane. However, maximization is needed in order to attain closer advancement to a membrane-based sensor device.

Non-uniform binding of single-stranded DNA binding proteins to hybrids of single-stranded DNA and single-walled carbon nanotubes observed by atomic force microscopy in air and in liquid

NASA Astrophysics Data System (ADS)

Umemura, Kazuo; Ishizaka, Kei; Nii, Daisuke; Izumi, Katsuki

2016-12-01

Using atomic force spectroscopy (AFM), we observed hybrids of single-stranded DNA (ssDNA) and single-walled carbon nanotubes (SWNTs) with or without protein molecules in air and in an aqueous solution. This is the first report of ssDNA-SWNT hybrids with proteins in solution analyzed by AFM. In the absence of protein, the height of the ssDNA-SWNT hybrids was 1.1 ± 0.3 nm and 2.4 ± 0.6 nm in air and liquid, respectively, suggesting that the ssDNA molecules adopted a flexible structure on the SWNT surface. In the presence of single-stranded DNA binding (SSB) proteins, the heights of the hybrids in air and liquid increased to 6.4 ± 3.1 nm and 10.0 ± 4.5 nm, respectively. The AFM images clearly showed binding of the SSB proteins to the ssDNA-SWNT hybrids. The morphology of the SSB-ssDNA-SWNT hybrids was non-uniform, particularly in aqueous solution. The variance of hybrid height was quantitatively estimated by cross-section analysis along the long-axis of each hybrid. The SSB-ssDNA-SWNT hybrids showed much larger variance than the ssDNA-SWNT hybrids.

Proton-bound dimers of nitrogen heterocyclic molecules: Substituent effects on the structures and binding energies of homodimers of diazine, triazine, and fluoropyridine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Attah, Isaac K.; Platt, Sean P.; Meot-Ner, Michael

2014-03-21

The bonding energies of proton-bound homodimers BH{sup +}B were measured by ion mobility equilibrium studies and calculated at the DFT B3LYP/6-311++G{sup **} level, for a series of nitrogen heterocyclic molecules (B) with electron-withdrawing in-ring N and on-ring F substituents. The binding energies (ΔH°{sub dissoc}) of the proton-bound dimers (BH{sup +}B) vary significantly, from 29.7 to 18.1 kcal/mol, decreasing linearly with decreasing the proton affinity of the monomer (B). This trend differs significantly from the constant binding energies of most homodimers of other organic nitrogen and oxygen bases. The experimentally measured ΔH°{sub dissoc} for (1,3-diazine){sub 2}H{sup +}, i.e., (pyrimidine){sub 2}H{sup +}more » and (3-F-pyridine){sub 2}H{sup +} are 22.7 and 23.0 kcal/mol, respectively. The measured ΔH°{sub dissoc} for the pyrimidine{sup ·+}(3-F-pyridine) radical cation dimer (19.2 kcal/mol) is signifcantly lower than that of the proton-bound homodimers of pyrimidine and 3-F-pyridine, reflecting the stronger interaction in the ionic H-bond of the protonated dimers. The calculated binding energies for (1,2-diazine){sub 2}H{sup +}, (pyridine){sub 2}H{sup +}, (2-F-pyridine){sub 2}H{sup +}, (3-F-pyridine){sub 2}H{sup +}, (2,6-di-F-pyridine){sub 2}H{sup +}, (4-F-pyridine){sub 2}H{sup +}, (1,3-diazine){sub 2}H{sup +}, (1,4-diazine){sub 2}H{sup +}, (1,3,5-triazine){sub 2}H{sup +}, and (pentafluoropyridine){sub 2}H{sup +} are 29.7, 24.9, 24.8, 23.3, 23.2, 23.0, 22.4, 21.9, 19.3, and 18.1 kcal/mol, respectively. The electron-withdrawing substituents form internal dipoles whose electrostatic interactions contribute to both the decreased proton affinities of (B) and the decreased binding energies of the protonated dimers BH{sup +}B. The bonding energies also vary with rotation about the hydrogen bond, and they decrease in rotamers where the internal dipoles of the components are aligned efficiently for inter-ring repulsion. For compounds substituted at the 3 or 4 (meta or para) positions, the lowest energy rotamers are T-shaped with the planes of the two rings rotated by 90° about the hydrogen bond, while the planar rotamers are weakened by repulsion between the ortho hydrogen atoms of the two rings. Conversely, in ortho-substituted (1,2-diazine){sub 2}H{sup +} and (2-F-pyridine){sub 2}H{sup +}, attractive interactions between the ortho (C–H) hydrogen atoms of one ring and the electronegative ortho atoms (N or F) of the other ring are stabilizing, and increase the protonated dimer binding energies by up to 4 kcal/mol. In all of the dimers, rotation about the hydrogen bond can involve a 2–4 kcal/mol barrier due to the relative energies of the rotamers.« less

Theoretical Studies of Hydrogen Storage Alloys.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jonsson, Hannes

Theoretical calculations were carried out to search for lightweight alloys that can be used to reversibly store hydrogen in mobile applications, such as automobiles. Our primary focus was on magnesium based alloys. While MgH{sub 2} is in many respects a promising hydrogen storage material, there are two serious problems which need to be solved in order to make it useful: (i) the binding energy of the hydrogen atoms in the hydride is too large, causing the release temperature to be too high, and (ii) the diffusion of hydrogen through the hydride is so slow that loading of hydrogen into themore » metal takes much too long. In the first year of the project, we found that the addition of ca. 15% of aluminum decreases the binding energy to the hydrogen to the target value of 0.25 eV which corresponds to release of 1 bar hydrogen gas at 100 degrees C. Also, the addition of ca. 15% of transition metal atoms, such as Ti or V, reduces the formation energy of interstitial H-atoms making the diffusion of H-atoms through the hydride more than ten orders of magnitude faster at room temperature. In the second year of the project, several calculations of alloys of magnesium with various other transition metals were carried out and systematic trends in stability, hydrogen binding energy and diffusivity established. Some calculations of ternary alloys and their hydrides were also carried out, for example of Mg{sub 6}AlTiH{sub 16}. It was found that the binding energy reduction due to the addition of aluminum and increased diffusivity due to the addition of a transition metal are both effective at the same time. This material would in principle work well for hydrogen storage but it is, unfortunately, unstable with respect to phase separation. A search was made for a ternary alloy of this type where both the alloy and the corresponding hydride are stable. Promising results were obtained by including Zn in the alloy.« less

Structures of small Pd Pt bimetallic clusters by Monte Carlo simulation

NASA Astrophysics Data System (ADS)

Cheng, Daojian; Huang, Shiping; Wang, Wenchuan

2006-11-01

Segregation phenomena of Pd-Pt bimetallic clusters with icosahedral and decahedral structures are investigated by using Monte Carlo method based on the second-moment approximation of the tight-binding (TB-SMA) potentials. The simulation results indicate that the Pd atoms generally lie on the surface of the smaller clusters. The three-shell onion-like structures are observed in 55-atom Pd-Pt bimetallic clusters, in which a single Pd atom is located in the center, and the Pt atoms are in the middle shell, while the Pd atoms are enriched on the surface. With the increase of Pd mole fraction in 55-atom Pd-Pt bimetallic clusters, the Pd atoms occupy the vertices of clusters first, then edge and center sites, and finally the interior shell. It is noticed that some decahedral structures can be transformed into the icosahedron-like structure at 300 and 500 K. Comparisons are made with previous experiments and theoretical studies of Pd-Pt bimetallic clusters.

Develop and Test a Solvent Accessible Surface Area-Based Model in Conformational Entropy Calculations

PubMed Central

Wang, Junmei; Hou, Tingjun

2012-01-01

It is of great interest in modern drug design to accurately calculate the free energies of protein-ligand or nucleic acid-ligand binding. MM-PBSA (Molecular Mechanics-Poisson Boltzmann Surface Area) and MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) have gained popularity in this field. For both methods, the conformational entropy, which is usually calculated through normal mode analysis (NMA), is needed to calculate the absolute binding free energies. Unfortunately, NMA is computationally demanding and becomes a bottleneck of the MM-PB/GBSA-NMA methods. In this work, we have developed a fast approach to estimate the conformational entropy based upon solvent accessible surface area calculations. In our approach, the conformational entropy of a molecule, S, can be obtained by summing up the contributions of all atoms, no matter they are buried or exposed. Each atom has two types of surface areas, solvent accessible surface area (SAS) and buried SAS (BSAS). The two types of surface areas are weighted to estimate the contribution of an atom to S. Atoms having the same atom type share the same weight and a general parameter k is applied to balance the contributions of the two types of surface areas. This entropy model was parameterized using a large set of small molecules for which their conformational entropies were calculated at the B3LYP/6-31G* level taking the solvent effect into account. The weighted solvent accessible surface area (WSAS) model was extensively evaluated in three tests. For the convenience, TS, the product of temperature T and conformational entropy S, were calculated in those tests. T was always set to 298.15 K through the text. First of all, good correlations were achieved between WSAS TS and NMA TS for 44 protein or nucleic acid systems sampled with molecular dynamics simulations (10 snapshots were collected for post-entropy calculations): the mean correlation coefficient squares (R2) was 0.56. As to the 20 complexes, the TS changes upon binding, TΔS, were also calculated and the mean R2 was 0.67 between NMA and WSAS. In the second test, TS were calculated for 12 proteins decoy sets (each set has 31 conformations) generated by the Rosetta software package. Again, good correlations were achieved for all decoy sets: the mean, maximum, minimum of R2 were 0.73, 0.89 and 0.55, respectively. Finally, binding free energies were calculated for 6 protein systems (the numbers of inhibitors range from 4 to 18) using four scoring functions. Compared to the measured binding free energies, the mean R2 of the six protein systems were 0.51, 0.47, 0.40 and 0.43 for MM-GBSA-WSAS, MM-GBSA-NMA, MM-PBSA-WSAS and MM-PBSA-NMA, respectively. The mean RMS errors of prediction were 1.19, 1.24, 1.41, 1.29 kcal/mol for the four scoring functions, correspondingly. Therefore, the two scoring functions employing WSAS achieved a comparable prediction performance to that of the scoring functions using NMA. It should be emphasized that no minimization was performed prior to the WSAS calculation in the last test. Although WSAS is not as rigorous as physical models such as quasi-harmonic analysis and thermodynamic integration (TI), it is computationally very efficient as only surface area calculation is involved and no structural minimization is required. Moreover, WSAS has achieved a comparable performance to normal mode analysis. We expect that this model could find its applications in the fields like high throughput screening (HTS), molecular docking and rational protein design. In those fields, efficiency is crucial since there are a large number of compounds, docking poses or protein models to be evaluated. A list of acronyms and abbreviations used in this work is provided for quick reference. PMID:22497310

Monovalent Strep-Tactin for strong and site-specific tethering in nanospectroscopy.

PubMed

Baumann, Fabian; Bauer, Magnus S; Milles, Lukas F; Alexandrovich, Alexander; Gaub, Hermann E; Pippig, Diana A

2016-01-01

Strep-Tactin, an engineered form of streptavidin, binds avidly to the genetically encoded peptide Strep-tag II in a manner comparable to streptavidin binding to biotin. These interactions have been used in protein purification and detection applications. However, in single-molecule studies, for example using atomic force microscopy-based single-molecule force spectroscopy (AFM-SMFS), the tetravalency of these systems impedes the measurement of monodispersed data. Here, we introduce a monovalent form of Strep-Tactin that harbours a unique binding site for Strep-tag II and a single cysteine that allows Strep-Tactin to specifically attach to the atomic force microscope cantilever and form a consistent pulling geometry to obtain homogeneous rupture data. Using AFM-SMFS, the mechanical properties of the interaction between Strep-tag II and monovalent Strep-Tactin were characterized. Rupture forces comparable to biotin:streptavidin unbinding were observed. Using titin kinase and green fluorescent protein, we show that monovalent Strep-Tactin is generally applicable to protein unfolding experiments. We expect monovalent Strep-Tactin to be a reliable anchoring tool for a range of single-molecule studies.

Monovalent Strep-Tactin for strong and site-specific tethering in nanospectroscopy

NASA Astrophysics Data System (ADS)

Baumann, Fabian; Bauer, Magnus S.; Milles, Lukas F.; Alexandrovich, Alexander; Gaub, Hermann E.; Pippig, Diana A.

2016-01-01

Strep-Tactin, an engineered form of streptavidin, binds avidly to the genetically encoded peptide Strep-tag II in a manner comparable to streptavidin binding to biotin. These interactions have been used in protein purification and detection applications. However, in single-molecule studies, for example using atomic force microscopy-based single-molecule force spectroscopy (AFM-SMFS), the tetravalency of these systems impedes the measurement of monodispersed data. Here, we introduce a monovalent form of Strep-Tactin that harbours a unique binding site for Strep-tag II and a single cysteine that allows Strep-Tactin to specifically attach to the atomic force microscope cantilever and form a consistent pulling geometry to obtain homogeneous rupture data. Using AFM-SMFS, the mechanical properties of the interaction between Strep-tag II and monovalent Strep-Tactin were characterized. Rupture forces comparable to biotin:streptavidin unbinding were observed. Using titin kinase and green fluorescent protein, we show that monovalent Strep-Tactin is generally applicable to protein unfolding experiments. We expect monovalent Strep-Tactin to be a reliable anchoring tool for a range of single-molecule studies.

Single-molecule conductance through multiple π-π-stacked benzene rings determined with direct electrode-to-benzene ring connections.

PubMed

Schneebeli, Severin T; Kamenetska, Maria; Cheng, Zhanling; Skouta, Rachid; Friesner, Richard A; Venkataraman, Latha; Breslow, Ronald

2011-02-23

Understanding electron transport across π-π-stacked systems will help to answer fundamental questions about biochemical redox processes and benefit the design of new materials and molecular devices. Herein we employed the STM break-junction technique to measure the single-molecule conductance of multiple π-π-stacked aromatic rings. We studied electron transport through up to four stacked benzene rings held together in an eclipsed fashion via a paracyclophane scaffold. We found that the strained hydrocarbons studied herein couple directly to gold electrodes during the measurements; hence, we did not require any heteroatom binding groups as electrical contacts. Density functional theory-based calculations suggest that the gold atoms of the electrodes bind to two neighboring carbon atoms of the outermost cyclophane benzene rings in η(2) fashion. Our measurements show an exponential decay of the conductance with an increasing number of stacked benzene rings, indicating a nonresonant tunneling mechanism. Furthermore, STM tip-substrate displacement data provide additional evidence that the electrodes bind to the outermost benzene rings of the π-π-stacked molecular wires.

Atomic-level insights into metabolite recognition and specificity of the SAM-II riboswitch

PubMed Central

Doshi, Urmi; Kelley, Jennifer M.; Hamelberg, Donald

2012-01-01

Although S-adenosylhomocysteine (SAH), a metabolic by-product of S-adenosylmethionine (SAM), differs from SAM only by a single methyl group and an overall positive charge, SAH binds the SAM-II riboswitch with more than 1000-fold less affinity than SAM. Using atomistic molecular dynamics simulations, we investigated the molecular basis of such high selectivity in ligand recognition by SAM-II riboswitch. The biosynthesis of SAM exclusively generates the (S,S) stereoisomer, and (S,S)-SAM can spontaneously convert to the (R,S) form. We, therefore, also examined the effects of (R,S)-SAM binding to SAM-II and its potential biological function. We find that the unfavorable loss in entropy in SAM-II binding is greater for (S,S)- and (R,S)-SAM than SAH, which is compensated by stabilizing electrostatic interactions with the riboswitch. The positively charged sulfonium moiety on SAM acts as the crucial anchor point responsible for the formation of key ionic interactions as it fits favorably in the negatively charged binding pocket. In contrast, SAH, with its lone pair of electrons on the sulfur, experiences repulsion in the binding pocket of SAM-II and is enthalpically destabilized. In the presence of SAH, similar to the unbound riboswitch, the pseudoknot structure of SAM-II is not completely formed, thus exposing the Shine-Dalgarno sequence. Unlike SAM, this may further facilitate ribosomal assembly and translation initiation. Our analysis of the conformational ensemble sampled by SAM-II in the absence of ligands and when bound to SAM or SAH reveals that ligand binding follows a combination of conformational selection and induced-fit mechanisms. PMID:22194311

Studies on binding mechanism between carotenoids from sea buckthorn and thermally treated α-lactalbumin

NASA Astrophysics Data System (ADS)

Dumitraşcu, Loredana; Ursache, Florentina Mihaela; Stănciuc, Nicoleta; Aprodu, Iuliana

2016-12-01

Sea buckthorn is a natural food ingredient rich in bioactive compounds such as carotenoids, tocopherols, sterols, flavonoids, lipids, vitamins, tannins and minerals. Herein, fluorescence and UV-vis techniques were used to study the interaction of heat treated α-lactalbumin (α-LA) with carotenoids from sea buckthorn berries extract (CSB) and β-carotene. Further atomic level details on the interaction between α-LA and β-carotene were obtained by means of molecular modelling techniques. The quenching rate constants, binding constants, and number of binding sites were calculated in the presence of CSB. The emission spectral studies revealed that, CSB have the ability to bind α-LA and form a ground state complex via static quenching process. Maximum degree of quenching was reached at 100 °C, where β-carotene and CSB quenched the Trp fluorescence of α-LA by 56% and 47%, respectively. In order to reveal the interaction between CSB and α-LA, the thermodynamic parameters were determined from the van't Hoff plot based on the temperature dependence of the binding constant. In agreement with the in silico observations, the thermodynamic parameters enabled us to consider that the association between α-LA and β-carotene is a spontaneous process driven by enthalpy, dominated mainly by the van der Waals interaction, but hydrophobic interactions might also be considered. The interaction between CSB and α-LA was further confirmed by UV-vis absorption spectra, where a blue shift of position was noticed at higher temperature suggesting the complex formation. The results provided here supply a better understanding of the binding of CSB to α-LA, which can be further exploited in designing new healthy food applications.