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Sample records for charmm general force

CHARMM-GUI ligand reader and modeler for CHARMM force field generation of small molecules.

PubMed

Kim, Seonghoon; Lee, Jumin; Jo, Sunhwan; Brooks, Charles L; Lee, Hui Sun; Im, Wonpil

2017-06-05

Reading ligand structures into any simulation program is often nontrivial and time consuming, especially when the force field parameters and/or structure files of the corresponding molecules are not available. To address this problem, we have developed Ligand Reader & Modeler in CHARMM-GUI. Users can upload ligand structure information in various forms (using PDB ID, ligand ID, SMILES, MOL/MOL2/SDF file, or PDB/mmCIF file), and the uploaded structure is displayed on a sketchpad for verification and further modification. Based on the displayed structure, Ligand Reader & Modeler generates the ligand force field parameters and necessary structure files by searching for the ligand in the CHARMM force field library or using the CHARMM general force field (CGenFF). In addition, users can define chemical substitution sites and draw substituents in each site on the sketchpad to generate a set of combinatorial structure files and corresponding force field parameters for throughput or alchemical free energy simulations. Finally, the output from Ligand Reader & Modeler can be used in other CHARMM-GUI modules to build a protein-ligand simulation system for all supported simulation programs, such as CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS, Desmond, OpenMM, and CHARMM/OpenMM. Ligand Reader & Modeler is available as a functional module of CHARMM-GUI at http://www.charmm-gui.org/input/ligandrm. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
CHARMM additive and polarizable force fields for biophysics and computer-aided drug design

PubMed Central

Vanommeslaeghe, K.

2014-01-01

Background Molecular Mechanics (MM) is the method of choice for computational studies of biomolecular systems owing to its modest computational cost, which makes it possible to routinely perform molecular dynamics (MD) simulations on chemical systems of biophysical and biomedical relevance. Scope of Review As one of the main factors limiting the accuracy of MD results is the empirical force field used, the present paper offers a review of recent developments in the CHARMM additive force field, one of the most popular bimolecular force fields. Additionally, we present a detailed discussion of the CHARMM Drude polarizable force field, anticipating a growth in the importance and utilization of polarizable force fields in the near future. Throughout the discussion emphasis is placed on the force fields’ parametrization philosophy and methodology. Major Conclusions Recent improvements in the CHARMM additive force field are mostly related to newly found weaknesses in the previous generation of additive force fields. Beyond the additive approximation is the newly available CHARMM Drude polarizable force field, which allows for MD simulations of up to 1 microsecond on proteins, DNA, lipids and carbohydrates. General Significance Addressing the limitations ensures the reliability of the new CHARMM36 additive force field for the types of calculations that are presently coming into routine computational reach while the availability of the Drude polarizable force fields offers a model that is an inherently more accurate model of the underlying physical forces driving macromolecular structures and dynamics. PMID:25149274
Is the Conformational Ensemble of Alzheimer’s Aβ10-40 Peptide Force Field Dependent?

PubMed Central

Siwy, Christopher M.

2017-01-01

By applying REMD simulations we have performed comparative analysis of the conformational ensembles of amino-truncated Aβ10-40 peptide produced with five force fields, which combine four protein parameterizations (CHARMM36, CHARMM22*, CHARMM22/cmap, and OPLS-AA) and two water models (standard and modified TIP3P). Aβ10-40 conformations were analyzed by computing secondary structure, backbone fluctuations, tertiary interactions, and radius of gyration. We have also calculated Aβ10-40 3JHNHα-coupling and RDC constants and compared them with their experimental counterparts obtained for the full-length Aβ1-40 peptide. Our study led us to several conclusions. First, all force fields predict that Aβ adopts unfolded structure dominated by turn and random coil conformations. Second, specific TIP3P water model does not dramatically affect secondary or tertiary Aβ10-40 structure, albeit standard TIP3P model favors slightly more compact states. Third, although the secondary structures observed in CHARMM36 and CHARMM22/cmap simulations are qualitatively similar, their tertiary interactions show little consistency. Fourth, two force fields, OPLS-AA and CHARMM22* have unique features setting them apart from CHARMM36 or CHARMM22/cmap. OPLS-AA reveals moderate β-structure propensity coupled with extensive, but weak long-range tertiary interactions leading to Aβ collapsed conformations. CHARMM22* exhibits moderate helix propensity and generates multiple exceptionally stable long- and short-range interactions. Our investigation suggests that among all force fields CHARMM22* differs the most from CHARMM36. Fifth, the analysis of 3JHNHα-coupling and RDC constants based on CHARMM36 force field with standard TIP3P model led us to an unexpected finding that in silico Aβ10-40 and experimental Aβ1-40 constants are generally in better agreement than these quantities computed and measured for identical peptides, such as Aβ1-40 or Aβ1-42. This observation suggests that the differences in the conformational ensembles of Aβ10-40 and Aβ1-40 are small and the former can be used as proxy of the full-length peptide. Based on this argument, we concluded that CHARMM36 force field with standard TIP3P model produces the most accurate representation of Aβ10-40 conformational ensemble. PMID:28085875
Parallel Tempering of Dark Matter from the Ebola Virus Proteome: Comparison of CHARMM36m and CHARMM22 Force Fields with Implicit Solvent.

PubMed

Olson, Mark A

2018-01-22

Intrinsically disordered proteins are characterized by their large manifold of thermally accessible conformations and their related statistical weights, making them an interesting target of simulation studies. To assess the development of a computational framework for modeling this distinct class of proteins, this work examines temperature-based replica-exchange simulations to generate a conformational ensemble of a 28-residue peptide from the Ebola virus protein VP35. Starting from a prefolded helix-β-turn-helix topology observed in a crystallographic assembly, the simulation strategy tested is the recently refined CHARMM36m force field combined with a generalized Born solvent model. A comparison of two replica-exchange methods is provided, where one is a traditional approach with a fixed set of temperatures and the other is an adaptive scheme in which the thermal windows are allowed to move in temperature space. The assessment is further extended to include a comparison with equivalent CHARMM22 simulation data sets. The analysis finds CHARMM36m to shift the minimum in the potential of mean force (PMF) to a lower fractional helicity compared with CHARMM22, while the latter showed greater conformational plasticity along the helix-forming reaction coordinate. Among the simulation models, only the adaptive tempering method with CHARMM36m found an ensemble of conformational heterogeneity consisting of transitions between α-helix-β-hairpin folds and unstructured states that produced a PMF of fractional fold propensity in qualitative agreement with circular dichroism experiments reporting a disordered peptide.
Dissolution study of active pharmaceutical ingredients using molecular dynamics simulations with classical force fields

NASA Astrophysics Data System (ADS)

Greiner, Maximilian; Elts, Ekaterina; Schneider, Julian; Reuter, Karsten; Briesen, Heiko

2014-11-01

The CHARMM, general Amber and OPLS force fields are evaluated for their suitability in simulating the molecular dynamics of the dissolution of the hydrophobic, small-molecule active pharmaceutical ingredients aspirin, ibuprofen, and paracetamol in aqueous media. The force fields are evaluated by comparison with quantum chemical simulations or experimental references on the basis of the following capabilities: accurately representing intra- and intermolecular interactions, appropriately reproducing crystal lattice parameters, adequately describing thermodynamic properties, and the qualitative description of the dissolution behavior. To make this approach easily accessible for evaluating the dissolution properties of novel drug candidates in the early stage of drug development, the force field parameter files are generated using online resources such as the SWISS PARAM servers, and the software packages ACPYPE and Maestro. All force fields are found to reproduce the intermolecular interactions with a reasonable degree of accuracy, with the general Amber and CHARMM force fields showing the best agreement with quantum mechanical calculations. A stable crystal bulk structure is obtained for all model substances, except for ibuprofen, where the reproductions of the lattice parameters and observed crystal stability are considerably poor for all force fields. The heat of solution used to evaluate the solid-to-solution phase transitions is found to be in qualitative agreement with the experimental data for all combinations tested, with the results being quantitatively optimum for the general Amber and CHARMM force fields. For aspirin and paracetamol, stable crystal-water interfaces were obtained. The (100), (110), (011) and (001) interfaces of aspirin or paracetamol and water were simulated for each force field for 30 ns. Although generally expected as a rare event, in some of the simulations, dissolution is observed at 310 K and ambient pressure conditions.
MATCH: An Atom- Typing Toolset for Molecular Mechanics Force Fields

PubMed Central

Yesselman, Joseph D.; Price, Daniel J.; Knight, Jennifer L.; Brooks, Charles L.

2011-01-01

We introduce a toolset of program libraries collectively titled MATCH (Multipurpose Atom-Typer for CHARMM) for the automated assignment of atom types and force field parameters for molecular mechanics simulation of organic molecules. The toolset includes utilities for the conversion from multiple chemical structure file formats into a molecular graph. A general chemical pattern-matching engine using this graph has been implemented whereby assignment of molecular mechanics atom types, charges and force field parameters is achieved by comparison against a customizable list of chemical fragments. While initially designed to complement the CHARMM simulation package and force fields by generating the necessary input topology and atom-type data files, MATCH can be expanded to any force field and program, and has core functionality that makes it extendable to other applications such as fragment-based property prediction. In the present work, we demonstrate the accurate construction of atomic parameters of molecules within each force field included in CHARMM36 through exhaustive cross validation studies illustrating that bond increment rules derived from one force field can be transferred to another. In addition, using leave-one-out substitution it is shown that it is also possible to substitute missing intra and intermolecular parameters with ones included in a force field to complete the parameterization of novel molecules. Finally, to demonstrate the robustness of MATCH and the coverage of chemical space offered by the recent CHARMM CGENFF force field (Vanommeslaeghe, et al., JCC., 2010, 31, 671–690), one million molecules from the PubChem database of small molecules are typed, parameterized and minimized. PMID:22042689
Intrinsically Disordered Protein Specific Force Field CHARMM36IDPSFF.

PubMed

Liu, Hao; Song, Dong; Lu, Hui; Luo, Ray; Chen, Hai-Feng

2018-05-28

Intrinsically disordered proteins (IDPs) are closely related to various human diseases. Because IDPs lack certain tertiary structure, it is difficult to use X-ray and NMR methods to measure their structures. Therefore, molecular dynamics simulation is a useful tool to study the conformer distribution of IDPs. However, most generic protein force fields were found to be insufficient in simulations of IDPs. Here we report our development for the CHARMM community. Our residue-specific IDP force field (CHARMM36IDPSFF) was developed based on the base generic force field with CMAP corrections of for all 20 naturally occurring amino acids. Multiple tests show that the simulated chemical shifts with the newly developed force field are in quantitative agreement with NMR experiment and are more accurate than the base generic force field. Comparison of J-couplings with previous work shows that CHARMM36IDPSFF and its corresponding base generic force field have their own advantages. In addition, CHARMM36IDPSFF simulations also agree with experiment for SAXS profiles and radii of gyration of IDPs. Detailed analysis shows that CHARMM36IDPSFF can sample more diverse and disordered conformers. These findings confirm that the newly developed force field can improve the balance of accuracy and efficiency for the conformer sampling of IDPs. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
CHARMM additive and polarizable force fields for biophysics and computer-aided drug design.

PubMed

Vanommeslaeghe, K; MacKerell, A D

2015-05-01

Molecular Mechanics (MM) is the method of choice for computational studies of biomolecular systems owing to its modest computational cost, which makes it possible to routinely perform molecular dynamics (MD) simulations on chemical systems of biophysical and biomedical relevance. As one of the main factors limiting the accuracy of MD results is the empirical force field used, the present paper offers a review of recent developments in the CHARMM additive force field, one of the most popular biomolecular force fields. Additionally, we present a detailed discussion of the CHARMM Drude polarizable force field, anticipating a growth in the importance and utilization of polarizable force fields in the near future. Throughout the discussion emphasis is placed on the force fields' parametrization philosophy and methodology. Recent improvements in the CHARMM additive force field are mostly related to newly found weaknesses in the previous generation of additive force fields. Beyond the additive approximation is the newly available CHARMM Drude polarizable force field, which allows for MD simulations of up to 1μs on proteins, DNA, lipids and carbohydrates. Addressing the limitations ensures the reliability of the new CHARMM36 additive force field for the types of calculations that are presently coming into routine computational reach while the availability of the Drude polarizable force fields offers an inherently more accurate model of the underlying physical forces driving macromolecular structures and dynamics. This article is part of a Special Issue entitled "Recent developments of molecular dynamics". Copyright © 2014 Elsevier B.V. All rights reserved.
Recent Developments and Applications of the CHARMM force fields

PubMed Central

Zhu, Xiao; Lopes, Pedro E.M.; MacKerell, Alexander D.

2011-01-01

Empirical force fields commonly used to describe the condensed phase properties of complex systems such as biological macromolecules are continuously being updated. Improvements in quantum mechanical (QM) methods used to generate target data, availability of new experimental target data, incorporation of new classes of compounds and new theoretical developments (eg. polarizable methods) make force-field development a dynamic domain of research. Accordingly, a number of improvements and extensions of the CHARMM force fields have occurred over the years. The objective of the present review is to provide an up-to-date overview of the CHARMM force fields. A limited presentation on the historical aspects of force fields will be given, including underlying methodologies and principles, along with a brief description of the strategies used for parameter development. This is followed by information on the CHARMM additive and polarizable force fields, including examples of recent applications of those force fields. PMID:23066428
Principal Component Analysis of Lipid Molecule Conformational Changes in Molecular Dynamics Simulations.

PubMed

Buslaev, Pavel; Gordeliy, Valentin; Grudinin, Sergei; Gushchin, Ivan

2016-03-08

Molecular dynamics simulations of lipid bilayers are ubiquitous nowadays. Usually, either global properties of the bilayer or some particular characteristics of each lipid molecule are evaluated in such simulations, but the structural properties of the molecules as a whole are rarely studied. Here, we show how a comprehensive quantitative description of conformational space and dynamics of a single lipid molecule can be achieved via the principal component analysis (PCA). We illustrate the approach by analyzing and comparing simulations of DOPC bilayers obtained using eight different force fields: all-atom generalized AMBER, CHARMM27, CHARMM36, Lipid14, and Slipids and united-atom Berger, GROMOS43A1-S3, and GROMOS54A7. Similarly to proteins, most of the structural variance of a lipid molecule can be described by only a few principal components. These major components are similar in different simulations, although there are notable distinctions between the older and newer force fields and between the all-atom and united-atom force fields. The DOPC molecules in the simulations generally equilibrate on the time scales of tens to hundreds of nanoseconds. The equilibration is the slowest in the GAFF simulation and the fastest in the Slipids simulation. Somewhat unexpectedly, the equilibration in the united-atom force fields is generally slower than in the all-atom force fields. Overall, there is a clear separation between the more variable previous generation force fields and significantly more similar new generation force fields (CHARMM36, Lipid14, Slipids). We expect that the presented approaches will be useful for quantitative analysis of conformations and dynamics of individual lipid molecules in other simulations of lipid bilayers.
How accurately do force fields represent protein side chain ensembles?

PubMed

Petrović, Dušan; Wang, Xue; Strodel, Birgit

2018-05-23

Although the protein backbone is the most fundamental part of the structure, the fine-tuning of side-chain conformations is important for protein function, for example, in protein-protein and protein-ligand interactions, and also in enzyme catalysis. While several benchmarks testing the performance of protein force fields for side chain properties have already been published, they often considered only a few force fields and were not tested against the same experimental observables; hence, they are not directly comparable. In this work, we explore the ability of twelve force fields, which are different flavors of AMBER, CHARMM, OPLS, or GROMOS, to reproduce average rotamer angles and rotamer populations obtained from extensive NMR studies of the 3 J and residual dipolar coupling constants for two small proteins: ubiquitin and GB3. Based on a total of 196 μs sampling time, our results reveal that all force fields identify the correct side chain angles, while the AMBER and CHARMM force fields clearly outperform the OPLS and GROMOS force fields in estimating rotamer populations. The three best force fields for representing the protein side chain dynamics are AMBER 14SB, AMBER 99SB*-ILDN, and CHARMM36. Furthermore, we observe that the side chain ensembles of buried amino acid residues are generally more accurately represented than those of the surface exposed residues. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.
Effects of force fields on the conformational and dynamic properties of amyloid β(1-40) dimer explored by replica exchange molecular dynamics simulations.

PubMed

Watts, Charles R; Gregory, Andrew; Frisbie, Cole; Lovas, Sándor

2018-03-01

The conformational space and structural ensembles of amyloid beta (Aβ) peptides and their oligomers in solution are inherently disordered and proven to be challenging to study. Optimum force field selection for molecular dynamics (MD) simulations and the biophysical relevance of results are still unknown. We compared the conformational space of the Aβ(1-40) dimers by 300 ns replica exchange MD simulations at physiological temperature (310 K) using: the AMBER-ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields. Statistical comparisons of simulation results to experimental data and previously published simulations utilizing the CHARMM22* and CHARMM36 force fields were performed. All force fields yield sampled ensembles of conformations with collision cross sectional areas for the dimer that are statistically significantly larger than experimental results. All force fields, with the exception of AMBER-ff99sb-ILDN (8.8 ± 6.4%) and CHARMM36 (2.7 ± 4.2%), tend to overestimate the α-helical content compared to experimental CD (5.3 ± 5.2%). Using the AMBER-ff99sb-NMR force field resulted in the greatest degree of variance (41.3 ± 12.9%). Except for the AMBER-ff99sb-NMR force field, the others tended to under estimate the expected amount of β-sheet and over estimate the amount of turn/bend/random coil conformations. All force fields, with the exception AMBER-ff99sb-NMR, reproduce a theoretically expected β-sheet-turn-β-sheet conformational motif, however, only the CHARMM22* and CHARMM36 force fields yield results compatible with collapse of the central and C-terminal hydrophobic cores from residues 17-21 and 30-36. Although analyses of essential subspace sampling showed only minor variations between force fields, secondary structures of lowest energy conformers are different. © 2017 Wiley Periodicals, Inc.
Thermal denaturing of mutant lysozyme with both the OPLSAA and the CHARMM force fields.

PubMed

Eleftheriou, Maria; Germain, Robert S; Royyuru, Ajay K; Zhou, Ruhong

2006-10-18

Biomolecular simulations enabled by massively parallel supercomputers such as BlueGene/L promise to bridge the gap between the currently accessible simulation time scale and the experimental time scale for many important protein folding processes. In this study, molecular dynamics simulations were carried out for both the wild-type and the mutant hen lysozyme (TRP62GLY) to study the single mutation effect on lysozyme stability and misfolding. Our thermal denaturing simulations at 400-500 K with both the OPLSAA and the CHARMM force fields show that the mutant structure is indeed much less stable than the wild-type, which is consistent with the recent urea denaturing experiment (Dobson et al. Science 2002, 295, 1719-1722; Nature 2003, 424, 783-788). Detailed results also reveal that the single mutation TRP62GLY first induces the loss of native contacts in the beta-domain region of the lysozyme protein at high temperatures, and then the unfolding process spreads into the alpha-domain region through Helix C. Even though the OPLSAA force field in general shows a more stable protein structure than does the CHARMM force field at high temperatures, the two force fields examined here display qualitatively similar results for the misfolding process, indicating that the thermal denaturing of the single mutation is robust and reproducible with various modern force fields.
Opening mechanism of adenylate kinase can vary according to selected molecular dynamics force field

NASA Astrophysics Data System (ADS)

Unan, Hulya; Yildirim, Ahmet; Tekpinar, Mustafa

2015-07-01

Adenylate kinase is a widely used test case for many conformational transition studies. It performs a large conformational transition between closed and open conformations while performing its catalytic function. To understand conformational transition mechanism and impact of force field choice on E. Coli adenylate kinase, we performed all-atom explicit solvent classical molecular dynamics simulations starting from the closed conformation with four commonly used force fields, namely, Amber99, Charmm27, Gromos53a6, Opls-aa. We carried out 40 simulations, each one 200 ns. We analyzed completely 12 of them that show full conformational transition from the closed state to the open one. Our study shows that different force fields can have a bias toward different transition pathways. Transition time scales, frequency of conformational transitions, order of domain motions and free energy landscapes of each force field may also vary. In general, Amber99 and Charmm27 behave similarly while Gromos53a6 results have a resemblance to the Opls-aa force field results.
Dendrimer Interactions with Lipid Bilayer: Comparison of Force Field and Effect of Implicit vs Explicit Solvation.

PubMed

Kanchi, Subbarao; Gosika, Mounika; Ayappa, K G; Maiti, Prabal K

2018-06-13

The understanding of dendrimer interactions with cell membranes has great importance in drug/gene delivery based therapeutics. Although molecular simulations have been used to understand the nature of dendrimer interactions with lipid membranes, its dependency on available force field parameters is poorly understood. In this study, we have carried out fully atomistic molecular dynamics (MD) simulations of a protonated G3 poly(amido amine) (PAMAM) dendrimer-dimyristoylphosphatidylcholine (DMPC) lipid bilayer complex using three different force fields (FFs) namely, CHARMM, GAFF, and GROMOS in the presence of explicit water to understand the structure of the lipid-dendrimer complex and nature of their interaction. CHARMM and GAFF dendrimers initially in contact with the lipid head groups were found to move away from the lipid bilayer during the course of simulation; however, the dendrimer remained strongly bound to the lipid head groups with the GROMOS FF. Potential of the mean force (PMF) computations of the dendrimer along the bilayer normal showed a repulsive barrier (∼20 kcal/mol) between dendrimer and lipid bilayer in the case of CHARMM and GAFF force fields. In contrast, an attractive interaction (∼40 kcal/mol) is obtained with the GROMOS force field, consistent with experimental observations of membrane binding observed with lower generation G3 PAMAM dendrimers. This difference with the GROMOS dendrimer is attributed to the strong dendrimer-lipid interaction and lowered surface hydration of the dendrimer. Assessing the role of solvent, we find that the CHARMM and GAFF dendrimers strongly bind to the lipid bilayer with an implicit solvent (Generalized Born) model, whereas binding is not observed with explicit water (TIP3P). The opposing nature of dendrimer-membrane interactions in the presence of explicit and implicit solvents demonstrates that hydration effects play an important role in modulating the dendrimer-lipid interaction warranting a case for refinement of the existing dendrimer/lipid force fields.
Rapid parameterization of small molecules using the Force Field Toolkit.

PubMed

Mayne, Christopher G; Saam, Jan; Schulten, Klaus; Tajkhorshid, Emad; Gumbart, James C

2013-12-15

The inability to rapidly generate accurate and robust parameters for novel chemical matter continues to severely limit the application of molecular dynamics simulations to many biological systems of interest, especially in fields such as drug discovery. Although the release of generalized versions of common classical force fields, for example, General Amber Force Field and CHARMM General Force Field, have posited guidelines for parameterization of small molecules, many technical challenges remain that have hampered their wide-scale extension. The Force Field Toolkit (ffTK), described herein, minimizes common barriers to ligand parameterization through algorithm and method development, automation of tedious and error-prone tasks, and graphical user interface design. Distributed as a VMD plugin, ffTK facilitates the traversal of a clear and organized workflow resulting in a complete set of CHARMM-compatible parameters. A variety of tools are provided to generate quantum mechanical target data, setup multidimensional optimization routines, and analyze parameter performance. Parameters developed for a small test set of molecules using ffTK were comparable to existing CGenFF parameters in their ability to reproduce experimentally measured values for pure-solvent properties (<15% error from experiment) and free energy of solvation (±0.5 kcal/mol from experiment). Copyright © 2013 Wiley Periodicals, Inc.
CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field

DOE PAGES

Lee, Jumin; Cheng, Xi; Swails, Jason M.; ...

2015-11-12

Here we report that proper treatment of nonbonded interactions is essential for the accuracy of molecular dynamics (MD) simulations, especially in studies of lipid bilayers. The use of the CHARMM36 force field (C36 FF) in different MD simulation programs can result in disagreements with published simulations performed with CHARMM due to differences in the protocols used to treat the long-range and 1-4 nonbonded interactions. In this study, we systematically test the use of the C36 lipid FF in NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM. A wide range of Lennard-Jones (LJ) cutoff schemes and integrator algorithms were tested to find themore » optimal simulation protocol to best match bilayer properties of six lipids with varying acyl chain saturation and head groups. MD simulations of a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer were used to obtain the optimal protocol for each program. MD simulations with all programs were found to reasonably match the DPPC bilayer properties (surface area per lipid, chain order parameters, and area compressibility modulus) obtained using the standard protocol used in CHARMM as well as from experiments. The optimal simulation protocol was then applied to the other five lipid simulations and resulted in excellent agreement between results from most simulation programs as well as with experimental data. AMBER compared least favorably with the expected membrane properties, which appears to be due to its use of the hard-truncation in the LJ potential versus a force-based switching function used to smooth the LJ potential as it approaches the cutoff distance. The optimal simulation protocol for each program has been implemented in CHARMM-GUI. This protocol is expected to be applicable to the remainder of the additive C36 FF including the proteins, nucleic acids, carbohydrates, and small molecules.« less
CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field.

PubMed

Lee, Jumin; Cheng, Xi; Swails, Jason M; Yeom, Min Sun; Eastman, Peter K; Lemkul, Justin A; Wei, Shuai; Buckner, Joshua; Jeong, Jong Cheol; Qi, Yifei; Jo, Sunhwan; Pande, Vijay S; Case, David A; Brooks, Charles L; MacKerell, Alexander D; Klauda, Jeffery B; Im, Wonpil

2016-01-12

Proper treatment of nonbonded interactions is essential for the accuracy of molecular dynamics (MD) simulations, especially in studies of lipid bilayers. The use of the CHARMM36 force field (C36 FF) in different MD simulation programs can result in disagreements with published simulations performed with CHARMM due to differences in the protocols used to treat the long-range and 1-4 nonbonded interactions. In this study, we systematically test the use of the C36 lipid FF in NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM. A wide range of Lennard-Jones (LJ) cutoff schemes and integrator algorithms were tested to find the optimal simulation protocol to best match bilayer properties of six lipids with varying acyl chain saturation and head groups. MD simulations of a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer were used to obtain the optimal protocol for each program. MD simulations with all programs were found to reasonably match the DPPC bilayer properties (surface area per lipid, chain order parameters, and area compressibility modulus) obtained using the standard protocol used in CHARMM as well as from experiments. The optimal simulation protocol was then applied to the other five lipid simulations and resulted in excellent agreement between results from most simulation programs as well as with experimental data. AMBER compared least favorably with the expected membrane properties, which appears to be due to its use of the hard-truncation in the LJ potential versus a force-based switching function used to smooth the LJ potential as it approaches the cutoff distance. The optimal simulation protocol for each program has been implemented in CHARMM-GUI. This protocol is expected to be applicable to the remainder of the additive C36 FF including the proteins, nucleic acids, carbohydrates, and small molecules.
Competition among Li+, Na+, K+ and Rb+ Monovalent Ions for DNA in Molecular Dynamics Simulations using the Additive CHARMM36 and Drude Polarizable Force Fields

PubMed Central

Savelyev, Alexey; MacKerell, Alexander D.

2015-01-01

In the present study we report on interactions of and competition between monovalent ions for two DNA sequences in MD simulations. Efforts included the development and validation of parameters for interactions among the first-group monovalent cations, Li+, Na+, K+ and Rb+, and DNA in the Drude polarizable and additive CHARMM36 force fields (FF). The optimization process targeted gas-phase QM interaction energies of various model compounds with ions and osmotic pressures of bulk electrolyte solutions of chemically relevant ions. The optimized ionic parameters are validated against counterion condensation theory and buffer exchange-atomic emission spectroscopy measurements providing quantitative data on the competitive association of different monovalent ions with DNA. Comparison between experimental and MD simulation results demonstrates that, compared to the additive CHARMM36 model, the Drude FF provides an improved description of the general features of the ionic atmosphere around DNA and leads to closer agreement with experiment on the ionic competition within the ion atmosphere. Results indicate the importance of extended simulation systems on the order of 25 Å beyond the DNA surface to obtain proper convergence of ion distributions. PMID:25751286
Automation of the CHARMM General Force Field (CGenFF) I: bond perception and atom typing

PubMed Central

Vanommeslaeghe, K.; MacKerell, A. D.

2012-01-01

Molecular mechanics force fields are widely used in computer-aided drug design for the study of drug-like molecules alone or interacting with biological systems. In simulations involving biological macromolecules, the biological part is typically represented by a specialized biomolecular force field, while the drug is represented by a matching general (organic) force field. In order to apply these general force fields to an arbitrary drug-like molecule, functionality for assignment of atom types, parameters and charges is required. In the present article, which is part I of a series of two, we present the algorithms for bond perception and atom typing for the CHARMM General Force Field (CGenFF). The CGenFF atom typer first associates attributes to the atoms and bonds in a molecule, such as valence, bond order, and ring membership among others. Of note are a number of features that are specifically required for CGenFF. This information is then used by the atom typing routine to assign CGenFF atom types based on a programmable decision tree. This allows for straightforward implementation of CGenFF’s complicated atom typing rules and for equally straightforward updating of the atom typing scheme as the force field grows. The presented atom typer was validated by assigning correct atom types on 477 model compounds including in the training set as well as 126 test-set molecules that were constructed to specifically verify its different components. The program may be utilized via an online implementation at https://www.paramchem.org/. PMID:23146088

Automation of the CHARMM General Force Field (CGenFF) I: bond perception and atom typing.

PubMed

Vanommeslaeghe, K; MacKerell, A D

2012-12-21

Molecular mechanics force fields are widely used in computer-aided drug design for the study of drug-like molecules alone or interacting with biological systems. In simulations involving biological macromolecules, the biological part is typically represented by a specialized biomolecular force field, while the drug is represented by a matching general (organic) force field. In order to apply these general force fields to an arbitrary drug-like molecule, functionality for assignment of atom types, parameters, and charges is required. In the present article, which is part I of a series of two, we present the algorithms for bond perception and atom typing for the CHARMM General Force Field (CGenFF). The CGenFF atom typer first associates attributes to the atoms and bonds in a molecule, such as valence, bond order, and ring membership among others. Of note are a number of features that are specifically required for CGenFF. This information is then used by the atom typing routine to assign CGenFF atom types based on a programmable decision tree. This allows for straightforward implementation of CGenFF's complicated atom typing rules and for equally straightforward updating of the atom typing scheme as the force field grows. The presented atom typer was validated by assigning correct atom types on 477 model compounds including in the training set as well as 126 test-set molecules that were constructed to specifically verify its different components. The program may be utilized via an online implementation at https://www.paramchem.org/ .
pmx: Automated protein structure and topology generation for alchemical perturbations

PubMed Central

Gapsys, Vytautas; Michielssens, Servaas; Seeliger, Daniel; de Groot, Bert L

2015-01-01

Computational protein design requires methods to accurately estimate free energy changes in protein stability or binding upon an amino acid mutation. From the different approaches available, molecular dynamics-based alchemical free energy calculations are unique in their accuracy and solid theoretical basis. The challenge in using these methods lies in the need to generate hybrid structures and topologies representing two physical states of a system. A custom made hybrid topology may prove useful for a particular mutation of interest, however, a high throughput mutation analysis calls for a more general approach. In this work, we present an automated procedure to generate hybrid structures and topologies for the amino acid mutations in all commonly used force fields. The described software is compatible with the Gromacs simulation package. The mutation libraries are readily supported for five force fields, namely Amber99SB, Amber99SB*-ILDN, OPLS-AA/L, Charmm22*, and Charmm36. PMID:25487359
CHARMM-GUI PDB manipulator for advanced modeling and simulations of proteins containing nonstandard residues.

PubMed

Jo, Sunhwan; Cheng, Xi; Islam, Shahidul M; Huang, Lei; Rui, Huan; Zhu, Allen; Lee, Hui Sun; Qi, Yifei; Han, Wei; Vanommeslaeghe, Kenno; MacKerell, Alexander D; Roux, Benoît; Im, Wonpil

2014-01-01

CHARMM-GUI, http://www.charmm-gui.org, is a web-based graphical user interface to prepare molecular simulation systems and input files to facilitate the usage of common and advanced simulation techniques. Since it is originally developed in 2006, CHARMM-GUI has been widely adopted for various purposes and now contains a number of different modules designed to setup a broad range of simulations including free energy calculation and large-scale coarse-grained representation. Here, we describe functionalities that have recently been integrated into CHARMM-GUI PDB Manipulator, such as ligand force field generation, incorporation of methanethiosulfonate spin labels and chemical modifiers, and substitution of amino acids with unnatural amino acids. These new features are expected to be useful in advanced biomolecular modeling and simulation of proteins. © 2014 Elsevier Inc. All rights reserved.
Parallel Tempering of Dark Matter from the Ebola Virus Proteome: Comparison of CHARMM36m and CHARMM22 Force Fields with Implicit Solvent and Coarse Grained Model

DTIC Science & Technology

2017-08-10

simulation models the conformational plasticity along the helix-forming reaction coordinate was limited by free - energy barriers. By comparison the coarse...revealed. The latter becomes evident in comparing the energy Z-score landscapes , where CHARMM22 simulation shows a manifold of shuttling...solvent simulations of calculating the charging free energy of protein conformations.33 Deviation to the protocol by modification of Born radii
Impact of 2′-hydroxyl sampling on the conformational properties of RNA: Update of the CHARMM all-atom additive force field for RNA

PubMed Central

Denning, Elizabeth J.; Priyakumar, U. Deva; Nilsson, Lennart; MacKerell, Alexander D.

2011-01-01

Here, we present an update of the CHARMM27 all-atom additive force field for nucleic acids that improves the treatment of RNA molecules. The original CHARMM27 force field parameters exhibit enhanced Watson-Crick (WC) base pair opening which is not consistent with experiment while analysis of MD simulations show the 2′-hydroxyl moiety to almost exclusively sample the O3′ orientation. Quantum mechanical studies of RNA related model compounds indicate the energy minimum associated with the O3′ orientation to be too favorable, consistent with the MD results. Optimization of the dihedral parameters dictating the energy of the 2′-hydroxyl proton targeting the QM data yielded several parameter sets, which sample both the base and O3′ orientations of the 2′-hydroxyl to varying degrees. Selection of the final dihedral parameters was based on reproduction of hydration behavior as related to a survey of crystallographic data and better agreement with experimental NMR J-coupling values. Application of the model, designated CHARMM36, to a collection of canonical and non-canonical RNA molecules reveals overall improved agreement with a range of experimental observables as compared to CHARMM27. The results also indicate the sensitivity of the conformational heterogeneity of RNA to the orientation of the 2′-hydroxyl moiety and support a model whereby the 2′-hydroxyl can enhance the probability of conformational transitions in RNA. PMID:21469161
Fragment-Based Docking: Development of the CHARMMing Web User Interface as a Platform for Computer-Aided Drug Design

PubMed Central

2015-01-01

Web-based user interfaces to scientific applications are important tools that allow researchers to utilize a broad range of software packages with just an Internet connection and a browser.1 One such interface, CHARMMing (CHARMM interface and graphics), facilitates access to the powerful and widely used molecular software package CHARMM. CHARMMing incorporates tasks such as molecular structure analysis, dynamics, multiscale modeling, and other techniques commonly used by computational life scientists. We have extended CHARMMing’s capabilities to include a fragment-based docking protocol that allows users to perform molecular docking and virtual screening calculations either directly via the CHARMMing Web server or on computing resources using the self-contained job scripts generated via the Web interface. The docking protocol was evaluated by performing a series of “re-dockings” with direct comparison to top commercial docking software. Results of this evaluation showed that CHARMMing’s docking implementation is comparable to many widely used software packages and validates the use of the new CHARMM generalized force field for docking and virtual screening. PMID:25151852
Fragment-based docking: development of the CHARMMing Web user interface as a platform for computer-aided drug design.

PubMed

Pevzner, Yuri; Frugier, Emilie; Schalk, Vinushka; Caflisch, Amedeo; Woodcock, H Lee

2014-09-22

Web-based user interfaces to scientific applications are important tools that allow researchers to utilize a broad range of software packages with just an Internet connection and a browser. One such interface, CHARMMing (CHARMM interface and graphics), facilitates access to the powerful and widely used molecular software package CHARMM. CHARMMing incorporates tasks such as molecular structure analysis, dynamics, multiscale modeling, and other techniques commonly used by computational life scientists. We have extended CHARMMing's capabilities to include a fragment-based docking protocol that allows users to perform molecular docking and virtual screening calculations either directly via the CHARMMing Web server or on computing resources using the self-contained job scripts generated via the Web interface. The docking protocol was evaluated by performing a series of "re-dockings" with direct comparison to top commercial docking software. Results of this evaluation showed that CHARMMing's docking implementation is comparable to many widely used software packages and validates the use of the new CHARMM generalized force field for docking and virtual screening.
CHARMM-GUI 10 Years for Biomolecular Modeling and Simulation

PubMed Central

Jo, Sunhwan; Cheng, Xi; Lee, Jumin; Kim, Seonghoon; Park, Sang-Jun; Patel, Dhilon S.; Beaven, Andrew H.; Lee, Kyu Il; Rui, Huan; Roux, Benoît; MacKerell, Alexander D.; Klauda, Jeffrey B.; Qi, Yifei

2017-01-01

CHARMM-GUI, http://www.charmm-gui.org, is a web-based graphical user interface that prepares complex biomolecular systems for molecular simulations. CHARMM-GUI creates input files for a number of programs including CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS, Desmond, OpenMM, and CHARMM/OpenMM. Since its original development in 2006, CHARMM-GUI has been widely adopted for various purposes and now contains a number of different modules designed to set up a broad range of simulations: (1) PDB Reader & Manipulator, Glycan Reader, and Ligand Reader & Modeler for reading and modifying molecules; (2) Quick MD Simulator, Membrane Builder, Nanodisc Builder, HMMM Builder, Monolayer Builder, Micelle Builder, and Hex Phase Builder for building all-atom simulation systems in various environments; (3) PACE CG Builder and Martini Maker for building coarse-grained simulation systems; (4) DEER Facilitator and MDFF/xMDFF Utilizer for experimentally guided simulations; (5) Implicit Solvent Modeler, PBEQ-Solver, and GCMC/BD Ion Simulator for implicit solvent related calculations; (6) Ligand Binder for ligand solvation and binding free energy simulations; and (7) Drude Prepper for preparation of simulations with the CHARMM Drude polarizable force field. Recently, new modules have been integrated into CHARMM-GUI, such as Glycolipid Modeler for generation of various glycolipid structures, and LPS Modeler for generation of lipopolysaccharide structures from various Gram-negative bacteria. These new features together with existing modules are expected to facilitate advanced molecular modeling and simulation thereby leading to an improved understanding of the molecular details of the structure and dynamics of complex biomolecular systems. Here, we briefly review these capabilities and discuss potential future directions in the CHARMM-GUI development project. PMID:27862047
CHARMM-GUI 10 years for biomolecular modeling and simulation.

PubMed

Jo, Sunhwan; Cheng, Xi; Lee, Jumin; Kim, Seonghoon; Park, Sang-Jun; Patel, Dhilon S; Beaven, Andrew H; Lee, Kyu Il; Rui, Huan; Park, Soohyung; Lee, Hui Sun; Roux, Benoît; MacKerell, Alexander D; Klauda, Jeffrey B; Qi, Yifei; Im, Wonpil

2017-06-05

CHARMM-GUI, http://www.charmm-gui.org, is a web-based graphical user interface that prepares complex biomolecular systems for molecular simulations. CHARMM-GUI creates input files for a number of programs including CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS, Desmond, OpenMM, and CHARMM/OpenMM. Since its original development in 2006, CHARMM-GUI has been widely adopted for various purposes and now contains a number of different modules designed to set up a broad range of simulations: (1) PDB Reader & Manipulator, Glycan Reader, and Ligand Reader & Modeler for reading and modifying molecules; (2) Quick MD Simulator, Membrane Builder, Nanodisc Builder, HMMM Builder, Monolayer Builder, Micelle Builder, and Hex Phase Builder for building all-atom simulation systems in various environments; (3) PACE CG Builder and Martini Maker for building coarse-grained simulation systems; (4) DEER Facilitator and MDFF/xMDFF Utilizer for experimentally guided simulations; (5) Implicit Solvent Modeler, PBEQ-Solver, and GCMC/BD Ion Simulator for implicit solvent related calculations; (6) Ligand Binder for ligand solvation and binding free energy simulations; and (7) Drude Prepper for preparation of simulations with the CHARMM Drude polarizable force field. Recently, new modules have been integrated into CHARMM-GUI, such as Glycolipid Modeler for generation of various glycolipid structures, and LPS Modeler for generation of lipopolysaccharide structures from various Gram-negative bacteria. These new features together with existing modules are expected to facilitate advanced molecular modeling and simulation thereby leading to an improved understanding of the structure and dynamics of complex biomolecular systems. Here, we briefly review these capabilities and discuss potential future directions in the CHARMM-GUI development project. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Lipopolysaccharide Membrane Building and Simulation

PubMed Central

Jo, Sunhwan; Wu, Emilia L.; Stuhlsatz, Danielle; Klauda, Jeffery B.; Widmalm, Göran; Im, Wonpil

2015-01-01

Summary While membrane simulations are widely employed to study the structure and dynamics of various lipid bilayers and membrane proteins in the bilayers, simulations of lipopolysaccharides (LPS) in membrane environments have been limited due to its structural complexity, difficulties in building LPS-membrane systems, and lack of appropriate molecular force field. In this work, as a first step to extend CHARMM-GUI Membrane Builder to incorporate LPS molecules and to explore their structures and dynamics in membrane environments using molecular dynamics simulations, we describe step-by-step procedures to build LPS bilayer systems using CHARMM and the recently developed CHARMM carbohydrate and lipid force fields. Such procedures are illustrated by building various bilayers of Escherichia coli O6 LPS and their preliminary simulation results are given in terms of per-LPS area and density distributions of various components along the membrane normal. PMID:25753722
Parameterization of an interfacial force field for accurate representation of peptide adsorption free energy on high-density polyethylene

PubMed Central

Abramyan, Tigran M.; Snyder, James A.; Yancey, Jeremy A.; Thyparambil, Aby A.; Wei, Yang; Stuart, Steven J.; Latour, Robert A.

2015-01-01

Interfacial force field (IFF) parameters for use with the CHARMM force field have been developed for interactions between peptides and high-density polyethylene (HDPE). Parameterization of the IFF was performed to achieve agreement between experimental and calculated adsorption free energies of small TGTG–X–GTGT host–guest peptides (T = threonine, G = glycine, and X = variable amino-acid residue) on HDPE, with ±0.5 kcal/mol agreement. This IFF parameter set consists of tuned nonbonded parameters (i.e., partial charges and Lennard–Jones parameters) for use with an in-house-modified CHARMM molecular dynamic program that enables the use of an independent set of force field parameters to control molecular behavior at a solid–liquid interface. The R correlation coefficient between the simulated and experimental peptide adsorption free energies increased from 0.00 for the standard CHARMM force field parameters to 0.88 for the tuned IFF parameters. Subsequent studies are planned to apply the tuned IFF parameter set for the simulation of protein adsorption behavior on an HDPE surface for comparison with experimental values of adsorbed protein orientation and conformation. PMID:25818122
Reparameterization of All-Atom Dipalmitoylphosphatidylcholine Lipid Parameters Enables Simulation of Fluid Bilayers at Zero Tension

PubMed Central

Sonne, Jacob; Jensen, Morten Ø.; Hansen, Flemming Y.; Hemmingsen, Lars; Peters, Günther H.

2007-01-01

Molecular dynamics simulations of dipalmitoylphosphatidylcholine (DPPC) lipid bilayers using the CHARMM27 force field in the tensionless isothermal-isobaric (NPT) ensemble give highly ordered, gel-like bilayers with an area per lipid of ∼48 Å2. To obtain fluid (Lα) phase properties of DPPC bilayers represented by the CHARMM energy function in this ensemble, we reparameterized the atomic partial charges in the lipid headgroup and upper parts of the acyl chains. The new charges were determined from the electron structure using both the Mulliken method and the restricted electrostatic potential fitting method. We tested the derived charges in molecular dynamics simulations of a fully hydrated DPPC bilayer. Only the simulation with the new restricted electrostatic potential charges shows significant improvements compared with simulations using the original CHARMM27 force field resulting in an area per lipid of 60.4 ± 0.1 Å2. Compared to the 48 Å2, the new value of 60.4 Å2 is in fair agreement with the experimental value of 64 Å2. In addition, the simulated order parameter profile and electron density profile are in satisfactory agreement with experimental data. Thus, the biologically more interesting fluid phase of DPPC bilayers can now be simulated in all-atom simulations in the NPT ensemble by employing our modified CHARMM27 force field. PMID:17400696
CHARMM Drude Polarizable Force Field for Aldopentofuranoses and Methyl-aldopentofuranosides

PubMed Central

Jana, Madhurima; MacKerell, Alexander D.

2015-01-01

An empirical all-atom CHARMM polarizable force filed for aldopentofuranoses and methyl-aldopentofuranosides based on the classical Drude oscillator is presented. A single electrostatic model is developed for eight different diastereoisomers of aldopentofuranoses by optimizing the existing electrostatic and bonded parameters as transferred from ethers, alcohols and hexopyranoses to reproduce quantum mechanical (QM) dipole moments, furanose-water interaction energies and conformational energies. Optimization of selected electrostatic and dihedral parameters was performed to generate a model for methyl-aldopentofuranosides. Accuracy of the model was tested by reproducing experimental data for crystal intramolecular geometries and lattice unit cell parameters, aqueous phase densities, and ring pucker and exocyclic rotamer populations as obtained from NMR experiments. In most cases the model is found to reproduce both QM data and experimental observables in an excellent manner, while for the remainder the level of agreement is in the satisfactory regimen. In aqueous phase simulations the monosaccharides have significantly enhanced dipoles as compared to the gas phase. The final model from this study is transferrable for future studies on carbohydrates and can be used with the existing CHARMM Drude polarizable force field for biomolecules. PMID:26018564
CHARMM: The Biomolecular Simulation Program

PubMed Central

Brooks, B.R.; Brooks, C.L.; MacKerell, A.D.; Nilsson, L.; Petrella, R.J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; Caflisch, A.; Caves, L.; Cui, Q.; Dinner, A.R.; Feig, M.; Fischer, S.; Gao, J.; Hodoscek, M.; Im, W.; Kuczera, K.; Lazaridis, T.; Ma, J.; Ovchinnikov, V.; Paci, E.; Pastor, R.W.; Post, C.B.; Pu, J.Z.; Schaefer, M.; Tidor, B.; Venable, R. M.; Woodcock, H. L.; Wu, X.; Yang, W.; York, D.M.; Karplus, M.

2009-01-01

CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. In addition, the CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This paper provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM paper in 1983. PMID:19444816
Parameterization of Ca+2-protein interactions for molecular dynamics simulations.

PubMed

Project, Elad; Nachliel, Esther; Gutman, Menachem

2008-05-01

Molecular dynamics simulations of Ca+2 ions near protein were performed with three force fields: GROMOS96, OPLS-AA, and CHARMM22. The simulations reveal major, force-field dependent, inconsistencies in the interaction between the Ca+2 ions with the protein. The variations are attributed to the nonbonded parameterizations of the Ca+2-carboxylates interactions. The simulations results were compared to experimental data, using the Ca+2-HCOO- equilibrium as a model. The OPLS-AA force field grossly overestimates the binding affinity of the Ca+2 ions to the carboxylate whereas the GROMOS96 and CHARMM22 force fields underestimate the stability of the complex. Optimization of the Lennard-Jones parameters for the Ca+2-carboxylate interactions were carried out, yielding new parameters which reproduce experimental data. Copyright 2007 Wiley Periodicals, Inc.
Simulation study of the structure and phase behavior of ceramide bilayers and the role of lipid head group chemistry

PubMed Central

Guo, Shan; Moore, Timothy C.; Iacovella, Christopher R.; Strickland, L. Anderson; McCabe, Clare

2014-01-01

Ceramides are known to be a key component of the stratum corneum, the outermost protective layer of the skin that controls barrier function. In this work, molecular dynamics simulations are used to examine the behavior of ceramide bilayers, focusing on non-hydroxy sphingosine (NS) and non-hydroxy phytosphingosine (NP) ceramides. Here, we propose a modified version of the CHARMM force field for ceramide simulation, which is directly compared to the more commonly used GROMOS-based force field of Berger (Biophys. J. 1997, 72); while both force fields are shown to closely match experiment from a structural standpoint at the physiological temperature of skin, the modified CHARMM force field is better able to capture the thermotropic phase transitions observed in experiment. The role of ceramide chemistry and its impact on structural ordering is examined by comparing ceramide NS to NP, using the validated CHARMM-based force field. These simulations demonstrate that changing from ceramide NS to NP results in changes to the orientation of the OH groups in the lipid headgroups. The arrangement of OH groups perpendicular to the bilayer normal for ceramide NP, verse parallel for NS, results in the formation of a distinct hydrogen bonding network, that is ultimately responsible for shifting the gel-to-liquid phase transition to higher temperature, in direct agreement with experiment. PMID:24501589
DNA Polymorphism: A Comparison of Force Fields for Nucleic Acids

PubMed Central

Reddy, Swarnalatha Y.; Leclerc, Fabrice; Karplus, Martin

2003-01-01

The improvements of the force fields and the more accurate treatment of long-range interactions are providing more reliable molecular dynamics simulations of nucleic acids. The abilities of certain nucleic acid force fields to represent the structural and conformational properties of nucleic acids in solution are compared. The force fields are AMBER 4.1, BMS, CHARMM22, and CHARMM27; the comparison of the latter two is the primary focus of this paper. The performance of each force field is evaluated first on its ability to reproduce the B-DNA decamer d(CGATTAATCG)2 in solution with simulations in which the long-range electrostatics were treated by the particle mesh Ewald method; the crystal structure determined by Quintana et al. (1992) is used as the starting point for all simulations. A detailed analysis of the structural and solvation properties shows how well the different force fields can reproduce sequence-specific features. The results are compared with data from experimental and previous theoretical studies. PMID:12609851
Development of a tuned interfacial force field parameter set for the simulation of protein adsorption to silica glass.

PubMed

Snyder, James A; Abramyan, Tigran; Yancey, Jeremy A; Thyparambil, Aby A; Wei, Yang; Stuart, Steven J; Latour, Robert A

2012-12-01

Adsorption free energies for eight host-guest peptides (TGTG-X-GTGT, with X = N, D, G, K, F, T, W, and V) on two different silica surfaces [quartz (100) and silica glass] were calculated using umbrella sampling and replica exchange molecular dynamics and compared with experimental values determined by atomic force microscopy. Using the CHARMM force field, adsorption free energies were found to be overestimated (i.e., too strongly adsorbing) by about 5-9 kcal/mol compared to the experimental data for both types of silica surfaces. Peptide adsorption behavior for the silica glass surface was then adjusted using a modified version of the CHARMM program, which we call dual force-field CHARMM, which allows separate sets of nonbonded parameters (i.e., partial charge and Lennard-Jones parameters) to be used to represent intra-phase and inter-phase interactions within a given molecular system. Using this program, interfacial force field (IFF) parameters for the peptide-silica glass systems were corrected to obtain adsorption free energies within about 0.5 kcal/mol of their respective experimental values, while IFF tuning for the quartz (100) surface remains for future work. The tuned IFF parameter set for silica glass will subsequently be used for simulations of protein adsorption behavior on silica glass with greater confidence in the balance between relative adsorption affinities of amino acid residues and the aqueous solution for the silica glass surface.
Development of a Tuned Interfacial Force Field Parameter Set for the Simulation of Protein Adsorption to Silica Glass

PubMed Central

Snyder, James A.; Abramyan, Tigran; Yancey, Jeremy A.; Thyparambil, Aby A.; Wei, Yang; Stuart, Steven J.; Latour, Robert A.

2012-01-01

Adsorption free energies for eight host–guest peptides (TGTG-X-GTGT, with X = N, D, G, K, F, T, W, and V) on two different silica surfaces [quartz (100) and silica glass] were calculated using umbrella sampling and replica exchange molecular dynamics and compared with experimental values determined by atomic force microscopy. Using the CHARMM force field, adsorption free energies were found to be overestimated (i.e., too strongly adsorbing) by about 5–9 kcal/mol compared to the experimental data for both types of silica surfaces. Peptide adsorption behavior for the silica glass surface was then adjusted using a modified version of the CHARMM program, which we call dual force-field CHARMM, which allows separate sets of nonbonded parameters (i.e., partial charge and Lennard-Jones parameters) to be used to represent intra-phase and inter-phase interactions within a given molecular system. Using this program, interfacial force field (IFF) parameters for the peptide-silica glass systems were corrected to obtain adsorption free energies within about 0.5 kcal/mol of their respective experimental values, while IFF tuning for the quartz (100) surface remains for future work. The tuned IFF parameter set for silica glass will subsequently be used for simulations of protein adsorption behavior on silica glass with greater confidence in the balance between relative adsorption affinities of amino acid residues and the aqueous solution for the silica glass surface. PMID:22941539
Secondary Structure of Rat and Human Amylin across Force Fields

PubMed Central

Hoffmann, Kyle Quynn; McGovern, Michael; Chiu, Chi-cheng; de Pablo, Juan J.

2015-01-01

The aggregation of human amylin has been strongly implicated in the progression of Type II diabetes. This 37-residue peptide forms a variety of secondary structures, including random coils, α-helices, and β-hairpins. The balance between these structures depends on the chemical environment, making amylin an ideal candidate to examine inherent biases in force fields. Rat amylin differs from human amylin by only 6 residues; however, it does not form fibrils. Therefore it provides a useful complement to human amylin in studies of the key events along the aggregation pathway. In this work, the free energy of rat and human amylin was determined as a function of α-helix and β-hairpin content for the Gromos96 53a6, OPLS-AA/L, CHARMM22/CMAP, CHARMM22*, Amberff99sb*-ILDN, and Amberff03w force fields using advanced sampling techniques, specifically bias exchange metadynamics. This work represents a first systematic attempt to evaluate the conformations and the corresponding free energy of a large, clinically relevant disordered peptide in solution across force fields. The NMR chemical shifts of rIAPP were calculated for each of the force fields using their respective free energy maps, allowing us to quantitatively assess their predictions. We show that the predicted distribution of secondary structures is sensitive to the choice of force-field: Gromos53a6 is biased towards β-hairpins, while CHARMM22/CMAP predicts structures that are overly α-helical. OPLS-AA/L favors disordered structures. Amberff99sb*-ILDN, AmberFF03w and CHARMM22* provide the balance between secondary structures that is most consistent with available experimental data. In contrast to previous reports, our findings suggest that the equilibrium conformations of human and rat amylin are remarkably similar, but that subtle differences arise in transient alpha-helical and beta-strand containing structures that the human peptide can more readily adopt. We hypothesize that these transient states enable dynamic pathways that facilitate the formation of aggregates and, eventually, amyloid fibrils. PMID:26221949

Secondary structure of rat and human amylin across force fields

DOE PAGES

Hoffmann, Kyle Quynn; McGovern, Michael; Chiu, Chi -cheng; ...

2015-07-29

The aggregation of human amylin has been strongly implicated in the progression of Type II diabetes. This 37-residue peptide forms a variety of secondary structures, including random coils, α-helices, and β-hairpins. The balance between these structures depends on the chemical environment, making amylin an ideal candidate to examine inherent biases in force fields. Rat amylin differs from human amylin by only 6 residues; however, it does not form fibrils. Therefore it provides a useful complement to human amylin in studies of the key events along the aggregation pathway. In this work, the free energy of rat and human amylin wasmore » determined as a function of α-helix and β-hairpin content for the Gromos96 53a6, OPLS-AA/L, CHARMM22/CMAP, CHARMM22*, Amberff99sb*-ILDN, and Amberff03w force fields using advanced sampling techniques, specifically bias exchange metadynamics. This work represents a first systematic attempt to evaluate the conformations and the corresponding free energy of a large, clinically relevant disordered peptide in solution across force fields. The NMR chemical shifts of rIAPP were calculated for each of the force fields using their respective free energy maps, allowing us to quantitatively assess their predictions. We show that the predicted distribution of secondary structures is sensitive to the choice of force-field: Gromos53a6 is biased towards β-hairpins, while CHARMM22/CMAP predicts structures that are overly α-helical. OPLS-AA/L favors disordered structures. Amberff99sb*-ILDN, AmberFF03w and CHARMM22* provide the balance between secondary structures that is most consistent with available experimental data. In contrast to previous reports, our findings suggest that the equilibrium conformations of human and rat amylin are remarkably similar, but that subtle differences arise in transient alpha-helical and beta-strand containing structures that the human peptide can more readily adopt. We hypothesize that these transient states enable dynamic pathways that facilitate the formation of aggregates and, eventually, amyloid fibrils.« less
Free energy profile of RNA hairpins: a molecular dynamics simulation study.

PubMed

Deng, Nan-Jie; Cieplak, Piotr

2010-02-17

RNA hairpin loops are one of the most abundant secondary structure elements and participate in RNA folding and protein-RNA recognition. To characterize the free energy surface of RNA hairpin folding at an atomic level, we calculated the potential of mean force (PMF) as a function of the end-to-end distance, by using umbrella sampling simulations in explicit solvent. Two RNA hairpins containing tetraloop cUUCGg and cUUUUg are studied with AMBER ff99 and CHARMM27 force fields. Experimentally, the UUCG hairpin is known to be significantly more stable than UUUU. In this study, the calculations using AMBER force field give a qualitatively correct description for the folding of two RNA hairpins, as the calculated PMF confirms the global stability of the folded structures and the resulting relative folding free energy is in quantitative agreement with the experimental result. The hairpin stabilities are also correctly differentiated by the more rapid molecular mechanics-Poisson Boltzmann-surface area approach, but the relative free energy estimated from this method is overestimated. The free energy profile shows that the native state basin and the unfolded state plateau are separated by a wide shoulder region, which samples a variety of native-like structures with frayed terminal basepair. The calculated PMF lacks major barriers that are expected near the transition regions, and this is attributed to the limitation of the 1-D reaction coordinate. The PMF results are compared with other studies of small RNA hairpins using kinetics method and coarse grained models. The two RNA hairpins described by CHARMM27 are significantly more deformable than those represented by AMBER. Compared with the AMBER results, the CHARMM27 calculated DeltaG(fold) for the UUUU tetraloop is in better agreement with the experimental results. However, the CHARMM27 calculation does not confirm the global stability of the experimental UUCG structure; instead, the extended conformations are predicted to be thermodynamically stable in solution. This finding is further supported by separate unrestrained CHARMM27 simulations, in which the UUCG hairpin unfolds spontaneously within 10 ns. The instability of the UUCG hairpin originates from the loop region, and propagates to the stem. The results of this study provide a molecular picture of RNA hairpin unfolding and reveal problems in the force field descriptions for the conformational energy of certain RNA hairpin. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Peptide aggregation and solvent electrostriction in a simple zwitterionic dipeptide via molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Tulip, P. R.; Bates, S. P.

2009-07-01

We investigate the structure of the glycyl-l-alanine dipeptide in aqueous solution at a 1:20 peptide:water concentration via classical, atomistic molecular dynamics simulations using the CHARMM22 force field, and compare to recent neutron diffraction data [S. E. McLain, A. K. Soper, and A. Watts, Eur. Biophys. J. 37, 647 (2008); S. E. McLain, A. K. Soper, I. Diadone, J. C. Smith, and A. Watts, Angew. Chem. Int. Ed. 47, 9059 (2008)]. Comparison between simulations and experiments is made using the static structure factor S (Q ) . The effect of water model (TIP3P, TIP4P, and SPC/E) upon the solution structure is investigated. Agreement between experiment and simulation is generally good across the entire Q range, although some model-dependent variation is observed, particularly in the predicted intensities of features in S (Q ) . Peptide aggregation is found to be driven by "hydrophilic" (often bifurcated) hydrogen bonds formed between carboxy and amine functional groups, although simulations suggest that the degree of aggregation is less than that observed experimentally. It is found that hydrophobic association is not significant, with hydrophobic hydration being preferred to association. Detailed examination of the solute structural motifs reveals the existence of bifurcated motifs that are suggested to be an artifact of the CHARMM force field, and may imply that classical force fields provide a flawed structural and dynamical description of such molecular fluids. Investigation of the water structure reveals the presence of an electrostrictive effect which manifests itself as an increase in the number of interstitial molecules in the water second coordination shell, in contradiction to suggestions that this phenomenon arises owing to hydrogen bond bending. Detailed analysis based upon two-dimensional distribution functions suggests an intimate link between the phenomenon of electrostriction and the behavior of water under high-pressure compression. We find the magnitude of the electrostrictive effect inferred from the neutron diffraction data to be greater than that found in the simulations. Investigation of the solvation structure suggests that the CHARMM force field overhydrates the terminal carboxy group, and that this overhydration is accompanied by the presence of bifurcated hydrogen bonds.
TopoGromacs: Automated Topology Conversion from CHARMM to GROMACS within VMD.

PubMed

Vermaas, Josh V; Hardy, David J; Stone, John E; Tajkhorshid, Emad; Kohlmeyer, Axel

2016-06-27

Molecular dynamics (MD) simulation engines use a variety of different approaches for modeling molecular systems with force fields that govern their dynamics and describe their topology. These different approaches introduce incompatibilities between engines, and previously published software bridges the gaps between many popular MD packages, such as between CHARMM and AMBER or GROMACS and LAMMPS. While there are many structure building tools available that generate topologies and structures in CHARMM format, only recently have mechanisms been developed to convert their results into GROMACS input. We present an approach to convert CHARMM-formatted topology and parameters into a format suitable for simulation with GROMACS by expanding the functionality of TopoTools, a plugin integrated within the widely used molecular visualization and analysis software VMD. The conversion process was diligently tested on a comprehensive set of biological molecules in vacuo. The resulting comparison between energy terms shows that the translation performed was lossless as the energies were unchanged for identical starting configurations. By applying the conversion process to conventional benchmark systems that mimic typical modestly sized MD systems, we explore the effect of the implementation choices made in CHARMM, NAMD, and GROMACS. The newly available automatic conversion capability breaks down barriers between simulation tools and user communities and allows users to easily compare simulation programs and leverage their unique features without the tedium of constructing a topology twice.
Current Status of Protein Force Fields for Molecular Dynamics

PubMed Central

Lopes, Pedro E.M.; Guvench, Olgun

2015-01-01

Summary The current status of classical force fields for proteins is reviewed. These include additive force fields as well as the latest developments in the Drude and AMOEBA polarizable force fields. Parametrization strategies developed specifically for the Drude force field are described and compared with the additive CHARMM36 force field. Results from molecular simulations of proteins and small peptides are summarized to illustrate the performance of the Drude and AMOEBA force fields. PMID:25330958
Force field dependent solution properties of glycine oligomers

PubMed Central

Drake, Justin A.

2015-01-01

Molecular simulations can be used to study disordered polypeptide systems and to generate hypotheses on the underlying structural and thermodynamic mechanisms that govern their function. As the number of disordered protein systems investigated with simulations increase, it is important to understand how particular force fields affect the structural properties of disordered polypeptides in solution. To this end, we performed a comparative structural analysis of Gly3 and Gly10 in aqueous solution from all-atom, microsecond MD simulations using the CHARMM 27 (C27), CHARMM 36 (C36), and Amber ff12SB force fields. For each force field, Gly3 and Gly10 were simulated for at least 300 ns and 1 μs, respectively. Simulating oligoglycines of two different lengths allows us to evaluate how force field effects depend on polypeptide length. Using a variety of structural metrics (e.g. end-to-end distance, radius of gyration, dihedral angle distributions), we characterize the distribution of oligoglycine conformers for each force field and show that each sample conformation space differently, yielding considerably different structural tendencies of the same oligoglycine model in solution. Notably, we find that C36 samples more extended oligoglycine structures than both C27 and ff12SB. PMID:25952623
ForConX: A forcefield conversion tool based on XML.

PubMed

Lesch, Volker; Diddens, Diddo; Bernardes, Carlos E S; Golub, Benjamin; Dequidt, Alain; Zeindlhofer, Veronika; Sega, Marcello; Schröder, Christian

2017-04-05

The force field conversion from one MD program to another one is exhausting and error-prone. Although single conversion tools from one MD program to another exist not every combination and both directions of conversion are available for the favorite MD programs Amber, Charmm, Dl-Poly, Gromacs, and Lammps. We present here a general tool for the force field conversion on the basis of an XML document. The force field is converted to and from this XML structure facilitating the implementation of new MD programs for the conversion. Furthermore, the XML structure is human readable and can be manipulated before continuing the conversion. We report, as testcases, the conversions of topologies for acetonitrile, dimethylformamide, and 1-ethyl-3-methylimidazolium trifluoromethanesulfonate comprising also Urey-Bradley and Ryckaert-Bellemans potentials. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
A nonadditive methanol force field: Bulk liquid and liquid-vapor interfacial properties via molecular dynamics simulations using a fluctuating charge model

NASA Astrophysics Data System (ADS)

Patel, Sandeep; Brooks, Charles L.

2005-01-01

We study the bulk and interfacial properties of methanol via molecular dynamics simulations using a CHARMM (Chemistry at HARvard Molecular Mechanics) fluctuating charge force field. We discuss the parametrization of the electrostatic model as part of the ongoing CHARMM development for polarizable protein force fields. The bulk liquid properties are in agreement with available experimental data and competitive with existing fixed-charge and polarizable force fields. The liquid density and vaporization enthalpy are determined to be 0.809 g/cm3 and 8.9 kcal/mol compared to the experimental values of 0.787 g/cm3 and 8.94 kcal/mol, respectively. The liquid structure as indicated by radial distribution functions is in keeping with the most recent neutron diffraction results; the force field shows a slightly more ordered liquid, necessarily arising from the enhanced condensed phase electrostatics (as evidenced by an induced liquid phase dipole moment of 0.7 D), although the average coordination with two neighboring molecules is consistent with the experimental diffraction study as well as with recent density functional molecular dynamics calculations. The predicted surface tension of 19.66±1.03 dyn/cm is slightly lower than the experimental value of 22.6 dyn/cm, but still competitive with classical force fields. The interface demonstrates the preferential molecular orientation of molecules as observed via nonlinear optical spectroscopic methods. Finally, via canonical molecular dynamics simulations, we assess the model's ability to reproduce the vapor-liquid equilibrium from 298 to 423 K, the simulation data then used to obtain estimates of the model's critical temperature and density. The model predicts a critical temperature of 470.1 K and critical density of 0.312 g/cm3 compared to the experimental values of 512.65 K and 0.279 g/cm3, respectively. The model underestimates the critical temperature by 8% and overestimates the critical density by 10%, and in this sense is roughly equivalent to the underlying fixed-charge CHARMM22 force field.
Effects of different force fields on the structural character of α synuclein β-hairpin peptide (35-56) in aqueous environment.

PubMed

Kundu, Sangeeta

2018-02-01

The hallmark of Parkinson's disease (PD) is the intracellular protein aggregation forming Lewy Bodies (LB) and Lewy neuritis which comprise mostly of a protein, alpha synuclein (α-syn). Molecular dynamics (MD) simulation methods can augment experimental techniques to understand misfolding and aggregation pathways with atomistic resolution. The quality of MD simulations for proteins and peptides depends greatly on the accuracy of empirical force fields. The aim of this work is to investigate the effects of different force fields on the structural character of β hairpin fragment of α-syn (residues 35-56) peptide in aqueous solution. Six independent MD simulations are done in explicit solvent using, AMBER03, AMBER99SB, GROMOS96 43A1, GROMOS96 53A6, OPLS-AA, and CHARMM27 force fields with CMAP corrections. The performance of each force field is assessed from several structural parameters such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), formation of β-turn, the stability of folded β-hairpin structure, and the favourable conformations obtained for different force fields. In this study, CMAP correction of CHARMM27 force field is found to overestimate the helical conformation, while GROMOS96 53A6 is found to most successfully capture the conformational dynamics of α-syn β-hairpin fragment as elicited from NMR.
Prediction of protein loop conformations using multiscale modeling methods with physical energy scoring functions.

PubMed

Olson, Mark A; Feig, Michael; Brooks, Charles L

2008-04-15

This article examines ab initio methods for the prediction of protein loops by a computational strategy of multiscale conformational sampling and physical energy scoring functions. Our approach consists of initial sampling of loop conformations from lattice-based low-resolution models followed by refinement using all-atom simulations. To allow enhanced conformational sampling, the replica exchange method was implemented. Physical energy functions based on CHARMM19 and CHARMM22 parameterizations with generalized Born (GB) solvent models were applied in scoring loop conformations extracted from the lattice simulations and, in the case of all-atom simulations, the ensemble of conformations were generated and scored with these models. Predictions are reported for 25 loop segments, each eight residues long and taken from a diverse set of 22 protein structures. We find that the simulations generally sampled conformations with low global root-mean-square-deviation (RMSD) for loop backbone coordinates from the known structures, whereas clustering conformations in RMSD space and scoring detected less favorable loop structures. Specifically, the lattice simulations sampled basins that exhibited an average global RMSD of 2.21 +/- 1.42 A, whereas clustering and scoring the loop conformations determined an RMSD of 3.72 +/- 1.91 A. Using CHARMM19/GB to refine the lattice conformations improved the sampling RMSD to 1.57 +/- 0.98 A and detection to 2.58 +/- 1.48 A. We found that further improvement could be gained from extending the upper temperature in the all-atom refinement from 400 to 800 K, where the results typically yield a reduction of approximately 1 A or greater in the RMSD of the detected loop. Overall, CHARMM19 with a simple pairwise GB solvent model is more efficient at sampling low-RMSD loop basins than CHARMM22 with a higher-resolution modified analytical GB model; however, the latter simulation method provides a more accurate description of the all-atom energy surface, yet demands a much greater computational cost. (c) 2007 Wiley Periodicals, Inc.
Comparison of Cellulose Iβ Simulations with Three Carbohydrate Force Fields.

PubMed

Matthews, James F; Beckham, Gregg T; Bergenstråhle-Wohlert, Malin; Brady, John W; Himmel, Michael E; Crowley, Michael F

2012-02-14

Molecular dynamics simulations of cellulose have recently become more prevalent due to increased interest in renewable energy applications, and many atomistic and coarse-grained force fields exist that can be applied to cellulose. However, to date no systematic comparison between carbohydrate force fields has been conducted for this important system. To that end, we present a molecular dynamics simulation study of hydrated, 36-chain cellulose Iβ microfibrils at room temperature with three carbohydrate force fields (CHARMM35, GLYCAM06, and Gromos 45a4) up to the near-microsecond time scale. Our results indicate that each of these simulated microfibrils diverge from the cellulose Iβ crystal structure to varying degrees under the conditions tested. The CHARMM35 and GLYCAM06 force fields eventually result in structures similar to those observed at 500 K with the same force fields, which are consistent with the experimentally observed high-temperature behavior of cellulose I. The third force field, Gromos 45a4, produces behavior significantly different from experiment, from the other two force fields, and from previously reported simulations with this force field using shorter simulation times and constrained periodic boundary conditions. For the GLYCAM06 force field, initial hydrogen-bond conformations and choice of electrostatic scaling factors significantly affect the rate of structural divergence. Our results suggest dramatically different time scales for convergence of properties of interest, which is important in the design of computational studies and comparisons to experimental data. This study highlights that further experimental and theoretical work is required to understand the structure of small diameter cellulose microfibrils typical of plant cellulose.
Influence of Force Fields and Quantum Chemistry Approach on Spectral Densities of BChl a in Solution and in FMO Proteins

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

Chandrasekaran, Suryanarayanan; Aghtar, Mortaza; Valleau, Stéphanie

2015-08-06

Studies on light-harvesting (LH) systems have attracted much attention after the finding of long-lived quantum coherences in the exciton dynamics of the Fenna–Matthews–Olson (FMO) complex. In this complex, excitation energy transfer occurs between the bacteriochlorophyll a (BChl a) pigments. Two quantum mechanics/molecular mechanics (QM/MM) studies, each with a different force-field and quantum chemistry approach, reported different excitation energy distributions for the FMO complex. To understand the reasons for these differences in the predicted excitation energies, we have carried out a comparative study between the simulations using the CHARMM and AMBER force field and the Zerner intermediate neglect of differential orbitalmore » (ZINDO)/S and time-dependent density functional theory (TDDFT) quantum chemistry methods. The calculations using the CHARMM force field together with ZINDO/S or TDDFT always show a wider spread in the energy distribution compared to those using the AMBER force field. High- or low-energy tails in these energy distributions result in larger values for the spectral density at low frequencies. A detailed study on individual BChl a molecules in solution shows that without the environment, the density of states is the same for both force field sets. Including the environmental point charges, however, the excitation energy distribution gets broader and, depending on the applied methods, also asymmetric. The excitation energy distribution predicted using TDDFT together with the AMBER force field shows a symmetric, Gaussian-like distribution.« less
NANOGOLD decorated by pHLIP peptide: comparative force field study.

PubMed

Kyrychenko, A

2015-05-21

The potential of gold nanoparticles (AuNPs) in therapeutic and diagnostic cancer applications is becoming increasingly recognized, which focuses on their efficient and specific delivery from passive accumulation in tumour tissue to directly targeting tumor-specific biomarkers. AuNPs functionalized by pH low insertion peptide (pHLIP) have recently revealed the capability of targeting acidic tissues and inserting into cell membranes. However, the structure of AuNP-pHLIP conjugates and fundamental gold-peptide interactions still remain unknown. In this study, we have developed a series of molecular dynamics (MD) models reproducing a small gold nanoparticle coupled to pHLIP. We focus on Au135 nanoparticles that comprise a nearly spherical Au core (diameter ∼ 1.4 nm) functionalized with a monomaleimide moiety, mimicking a commercially available monomaleimido NANOGOLD® labelling agent. To probe the structure and folding of pHLIP, which is attached covalently to the maleimide NANOGOLD particle, we have benchmarked the performances of a series of popular, all-atom force fields (FF), including those of OPLS-AA, AMBER03, three variations of CHARMM FFs, as well as united-atom GROMOS G53A6 FF. We found that CHARMMs and OPLSAA FFs predict that in an aqueous salt solution at a neutral pH, pHLIP is partially bound onto the gold surface through some short hydrophobic peptide stretches, while at the same time, a large portion of peptide remains in solution. In contrast, AMBER03 and G53A6 FFs revealed the formation of compact, tightly bound peptide configurations adsorbed onto the nanoparticle core. To reproduce the experimental physical picture of the peptide adsorption onto gold in unfolded and unstructured conformations, our study suggests CHARMM36 and OPLS-AA FFs as a tool of choice for the computational studies of NANOGOLD decorated by pHLIP.
Potential of mean force analysis of the self-association of leucine-rich transmembrane α-helices: difference between atomistic and coarse-grained simulations.

PubMed

Nishizawa, Manami; Nishizawa, Kazuhisa

2014-08-21

Interaction of transmembrane (TM) proteins is important in many biological processes. Large-scale computational studies using coarse-grained (CG) simulations are becoming popular. However, most CG model parameters have not fully been calibrated with respect to lateral interactions of TM peptide segments. Here, we compare the potential of mean forces (PMFs) of dimerization of TM helices obtained using a MARTINI CG model and an atomistic (AT) Berger lipids-OPLS/AA model (AT(OPLS)). For helical, tryptophan-flanked, leucine-rich peptides (WL15 and WALP15) embedded in a parallel configuration in an octane slab, the AT(OPLS) PMF profiles showed a shallow minimum (with a depth of approximately 3 kJ/mol; i.e., a weak tendency to dimerize). A similar analysis using the CHARMM36 all-atom model (AT(CHARMM)) showed comparable results. In contrast, the CG analysis generally showed steep PMF curves with depths of approximately 16-22 kJ/mol, suggesting a stronger tendency to dimerize compared to the AT model. This CG > AT discrepancy in the propensity for dimerization was also seen for dilauroylphosphatidylcholine (DLPC)-embedded peptides. For a WL15 (and WALP15)/DLPC bilayer system, AT(OPLS) PMF showed a repulsive mean force for a wide range of interhelical distances, in contrast to the attractive forces observed in the octane system. The change from the octane slab to the DLPC bilayer also mitigated the dimerization propensity in the CG system. The dimerization energies of CG (AALALAA)3 peptides in DLPC and dioleoylphosphatidylcholine bilayers were in good agreement with previous experimental data. The lipid headgroup, but not the length of the lipid tails, was a key causative factor contributing to the differences between octane and DLPC. Furthermore, the CG model, but not the AT model, showed high sensitivity to changes in amino acid residues located near the lipid-water interface and hydrophobic mismatch between the peptides and membrane. These findings may help interpret CG and AT simulation results on membrane proteins.
ff14IDPs Force Field Improving the Conformation Sampling of Intrinsically Disordered Proteins

PubMed Central

Song, Dong; Wang, Wei; Ye, Wei; Ji, Dingjue; Luo, Ray; Chen, Hai-Feng

2017-01-01

Intrinsically disordered proteins (IDPs) are proteins which lack of specific tertiary structure and unable to fold spontaneously without the partner binding. These IDPs are found to associate with various diseases, such as diabetes, cancer, and neurodegenerative diseases. However, current widely used force fields, such as ff99SB, ff14SB, OPLS/AA, and Charmm27 are insufficient in sampling the conformational characters of IDPs. In this study, the CMAP method was used to correct the φ/ψ distributions of disorder-promoting amino acids. The simulation results show that the force filed parameters (ff14IDPs) can improve the φ/ψ distributions of the disorder-promoting amino acids, with RMSD less than 0.10% relative to the benchmark data of IDPs. Further test suggests that the calculated secondary chemical shifts under ff14IDPs force field are in quantitative agreement with the data of NMR experiment for five tested systems. In addition, the simulation results show that ff14IDPs can still be used to model structural proteins, such as tested lysozyme and ubiquitin, with better performance in coil regions than the original general Amber force field ff14SB. These findings confirm that the newly developed Amber ff14IDPs force field is a robust model for improving the conformation sampling of IDPs. PMID:27484738
Improving the Force Field Description of Tyrosine-Choline Cation-π Interactions: QM Investigation of Phenol-N(Me)4+ Interactions.

PubMed

Khan, Hanif M; Grauffel, Cédric; Broer, Ria; MacKerell, Alexander D; Havenith, Remco W A; Reuter, Nathalie

2016-11-08

Cation-π interactions between tyrosine amino acids and compounds containing N,N,N-trimethylethanolammonium (N(CH 3 ) 3 ) are involved in the recognition of histone tails by chromodomains and in the recognition of phosphatidylcholine (PC) phospholipids by membrane-binding proteins. Yet, the lack of explicit polarization or charge transfer effects in molecular mechanics force fields raises questions about the reliability of the representation of these interactions in biomolecular simulations. Here, we investigate the nature of phenol-tetramethylammonium (TMA) interactions using quantum mechanical (QM) calculations, which we also use to evaluate the accuracy of the additive CHARMM36 and Drude polarizable force fields in modeling tyrosine-choline interactions. We show that the potential energy surface (PES) obtained using SAPT2+/aug-cc-pVDZ compares well with the large basis-set CCSD(T) PES when TMA approaches the phenol ring perpendicularly. Furthermore, the SAPT energy decomposition reveals comparable contributions from electrostatics and dispersion in phenol-TMA interactions. We then compared the SAPT2+/aug-cc-pVDZ PES obtained along various approach directions to the corresponding PES obtained with CHARMM, and we show that the force field accurately reproduces the minimum distances while the interaction energies are underestimated. The use of the Drude polarizable force field significantly improves the interaction energies but decreases the agreement on distances at energy minima. The best agreement between force field and QM PES is obtained by modifying the Lennard-Jones terms for atom pairs involved in the phenol-TMA cation-π interactions. This is further shown to improve the correlation between the occupancy of tyrosine-choline cation-π interactions obtained from molecular dynamics simulations of a bilayer-bound bacterial phospholipase and experimental affinity data of the wild-type protein and selected mutants.
Molecular Dynamics in Physiological Solutions: Force Fields, Alkali Metal Ions, and Ionic Strength.

PubMed

Zhang, Chao; Raugei, Simone; Eisenberg, Bob; Carloni, Paolo

2010-07-13

The monovalent ions Na(+) and K(+) and Cl(-) are present in any living organism. The fundamental thermodynamic properties of solutions containing such ions is given as the excess (electro-)chemical potential differences of single ions at finite ionic strength. This quantity is key for many biological processes, including ion permeation in membrane ion channels and DNA-protein interaction. It is given by a chemical contribution, related to the ion activity, and an electric contribution, related to the Galvani potential of the water/air interface. Here we investigate molecular dynamics based predictions of these quantities by using a variety of ion/water force fields commonly used in biological simulation, namely the AMBER (the newly developed), CHARMM, OPLS, Dang95 with TIP3P, and SPC/E water. Comparison with experiment is made with the corresponding values for salts, for which data are available. The calculations based on the newly developed AMBER force field with TIP3P water agrees well with experiment for both KCl and NaCl electrolytes in water solutions, as previously reported. The simulations based on the CHARMM-TIP3P and Dang95-SPC/E force fields agree well for the KCl and NaCl solutions, respectively. The other models are not as accurate. Single cations excess (electro-)chemical potential differences turn out to be similar for all the force fields considered here. In the case of KCl, the calculated electric contribution is consistent with higher level calculations. Instead, such agreement is not found with NaCl. Finally, we found that the calculated activities for single Cl(-) ions turn out to depend clearly on the type of counterion used, with all the force fields investigated. The implications of these findings for biomolecular systems are discussed.
Reparameterization of Solute—Solute Interactions for Amino Acid-Sugar Systems Using Isopiestic Osmotic Pressure Molecular Dynamics Simulations

PubMed Central

Lay, Wesley K.; Miller, Mark S.

2018-01-01

AMBER/GLYCAM and CHARMM are popular force fields for simulations of amino acids and sugars. Here we report excessively attractive amino acid-sugar interactions in both force fields, and corrections to nonbonded interactions that match experimental osmotic pressures of mixed aqueous solutions of diglycine and sucrose. The modified parameters also improve the ΔGtrans of diglycine from water to aqueous sucrose and, with AMBERff99SB/GLYCAM06, eliminate a caging effect seen in previous simulations of the protein ubiquitin with glucose. PMID:28437100
Optimization of the GBMV2 implicit solvent force field for accurate simulation of protein conformational equilibria.

PubMed

Lee, Kuo Hao; Chen, Jianhan

2017-06-15

Accurate treatment of solvent environment is critical for reliable simulations of protein conformational equilibria. Implicit treatment of solvation, such as using the generalized Born (GB) class of models arguably provides an optimal balance between computational efficiency and physical accuracy. Yet, GB models are frequently plagued by a tendency to generate overly compact structures. The physical origins of this drawback are relatively well understood, and the key to a balanced implicit solvent protein force field is careful optimization of physical parameters to achieve a sufficient level of cancellation of errors. The latter has been hampered by the difficulty of generating converged conformational ensembles of non-trivial model proteins using the popular replica exchange sampling technique. Here, we leverage improved sampling efficiency of a newly developed multi-scale enhanced sampling technique to re-optimize the generalized-Born with molecular volume (GBMV2) implicit solvent model with the CHARMM36 protein force field. Recursive optimization of key GBMV2 parameters (such as input radii) and protein torsion profiles (via the CMAP torsion cross terms) has led to a more balanced GBMV2 protein force field that recapitulates the structures and stabilities of both helical and β-hairpin model peptides. Importantly, this force field appears to be free of the over-compaction bias, and can generate structural ensembles of several intrinsically disordered proteins of various lengths that seem highly consistent with available experimental data. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
All-Atom Polarizable Force Field for DNA Based on the Classical Drude Oscillator Model

PubMed Central

Savelyev, Alexey; MacKerell, Alexander D.

2014-01-01

Presented is a first generation atomistic force field for DNA in which electronic polarization is modeled based on the classical Drude oscillator formalism. The DNA model is based on parameters for small molecules representative of nucleic acids, including alkanes, ethers, dimethylphosphate, and the nucleic acid bases and empirical adjustment of key dihedral parameters associated with the phosphodiester backbone, glycosidic linkages and sugar moiety of DNA. Our optimization strategy is based on achieving a compromise between satisfying the properties of the underlying model compounds in the gas phase targeting QM data and reproducing a number of experimental properties of DNA duplexes in the condensed phase. The resulting Drude force field yields stable DNA duplexes on the 100 ns time scale and satisfactorily reproduces (1) the equilibrium between A and B forms of DNA and (2) transitions between the BI and BII sub-states of B form DNA. Consistency with the gas phase QM data for the model compounds is significantly better for the Drude model as compared to the CHARMM36 additive force field, which is suggested to be due to the improved response of the model to changes in the environment associated with the explicit inclusion of polarizability. Analysis of dipole moments associated with the nucleic acid bases shows the Drude model to have significantly larger values than those present in CHARMM36, with the dipoles of individual bases undergoing significant variations during the MD simulations. Additionally, the dipole moment of water was observed to be perturbed in the grooves of DNA. PMID:24752978

In Silico Design of Smart Binders to Anthrax PA

DTIC Science & Technology

2012-09-01

nanosecond(ns) molecular dynamics simulation in the NPT ensemble (constant particle number, pressure, and temperature) at 300K, with the CHARMM force...protective antigen (PA). Before the docking runs, the DS23 peptide was simulated using molecular dynamics to generate an ensemble of structures...structure), we do not see a large amount of structural change when using molecular dynamics after Rosetta docking. We note that this RMSD does not take
Insight into the Properties of Cardiolipin Containing Bilayers from Molecular Dynamics Simulations, Using a Hybrid All-Atom/United-Atom Force Field.

PubMed

Aguayo, Daniel; González-Nilo, Fernando D; Chipot, Christophe

2012-05-08

Simulation of three models of cardiolipin (CL) containing membranes using a new set of parameters for tetramyristoyl and tetraoleoyl CLs has been developed in the framework of the united-atom CHARMM27-UA and the all-atom CHARMM36 force fields with the aim of performing molecular dynamics (MD) simulations of cardiolipin-containing mixed-lipid membranes. The new parameters use a hybrid representation of all-atom head groups in conjunction with implicit-hydrogen united-atom (UA) to describe the oleoyl and myristoyl chains of the CLs, in lieu of the fully atomistic description, thereby allowing longer simulations to be undertaken. The physicochemical properties of the bilayers were determined and compared with previously reported data. Furthermore, using tetramyristoyl CL mixed with POPG and POPE lipids, a mitochondrial membrane was simulated. The results presented here show the different behavior of the bilayers as a result of the lipid composition, where the length of the acyl chain and the conformation of the headgroup can be associated with the mitochondrial membrane properties. The new hybrid CL parameters prove to be well suited for the simulation of the molecular structure of CL-containing bilayers and can be extended to other lipid bilayers composed of CLs with different acyl chains or alternate head groups.
Computational and Experimental Characterization of Ribosomal DNA and RNA G-Quadruplexes

NASA Astrophysics Data System (ADS)

Cho, Samuel

DNA G-quadruplexes in human telomeres and gene promoters are being extensively studied for their role in controlling the growth of cancer cells. Recent studies strongly suggest that guanine (G)-rich genes encoding pre-ribosomal RNA (pre-rRNA) are a potential anticancer target through the inhibition of RNA polymerase I (Pol I) in ribosome biogenesis. However, the structures of ribosomal G-quadruplexes at atomic resolution are unknown, and very little biophysical characterization has been performed on them to date. Here, we have modeled two putative rDNA G-quadruplex structures, NUC 19P and NUC 23P, which we observe via circular dichroism (CD) spectroscopy to adopt a predominantly parallel topology, and their counterpart rRNA. To validate and refine the putative ribosomal G-quadruplex structures, we performed all-atom molecular dynamics (MD) simulations using the CHARMM36 force field in the presence and absence of stabilizing K + or Na + ions. We optimized the CHARMM36 force field K + parameters to be more consistent with quantum mechanical calculations (and the polarizable Drude model force field) so that the K + ion is predominantly in the G-quadruplex channel. Our MD simulations show that the rDNA G-quadruplex have more well-defined, predominantly parallel-topology structures than rRNA and NUC 19P is more structured than NUC 23P, which features extended loops. Our study demonstrates that they are both potential targets for the design of novel chemotherapeutics.
Cutoff size need not strongly influence molecular dynamics results for solvated polypeptides.

PubMed

Beck, David A C; Armen, Roger S; Daggett, Valerie

2005-01-18

The correct treatment of van der Waals and electrostatic nonbonded interactions in molecular force fields is essential for performing realistic molecular dynamics (MD) simulations of solvated polypeptides. The most computationally tractable treatment of nonbonded interactions in MD utilizes a spherical distance cutoff (typically, 8-12 A) to reduce the number of pairwise interactions. In this work, we assess three spherical atom-based cutoff approaches for use with all-atom explicit solvent MD: abrupt truncation, a CHARMM-style electrostatic shift truncation, and our own force-shifted truncation. The chosen system for this study is an end-capped 17-residue alanine-based alpha-helical peptide, selected because of its use in previous computational and experimental studies. We compare the time-averaged helical content calculated from these MD trajectories with experiment. We also examine the effect of varying the cutoff treatment and distance on energy conservation. We find that the abrupt truncation approach is pathological in its inability to conserve energy. The CHARMM-style shift truncation performs quite well but suffers from energetic instability. On the other hand, the force-shifted spherical cutoff method conserves energy, correctly predicts the experimental helical content, and shows convergence in simulation statistics as the cutoff is increased. This work demonstrates that by using proper and rigorous techniques, it is possible to correctly model polypeptide dynamics in solution with a spherical cutoff. The inherent computational advantage of spherical cutoffs over Ewald summation (and related) techniques is essential in accessing longer MD time scales.
Improved model of hydrated calcium ion for molecular dynamics simulations using classical biomolecular force fields.

PubMed

Yoo, Jejoong; Wilson, James; Aksimentiev, Aleksei

2016-10-01

Calcium ions (Ca(2+) ) play key roles in various fundamental biological processes such as cell signaling and brain function. Molecular dynamics (MD) simulations have been used to study such interactions, however, the accuracy of the Ca(2+) models provided by the standard MD force fields has not been rigorously tested. Here, we assess the performance of the Ca(2+) models from the most popular classical force fields AMBER and CHARMM by computing the osmotic pressure of model compounds and the free energy of DNA-DNA interactions. In the simulations performed using the two standard models, Ca(2+) ions are seen to form artificial clusters with chloride, acetate, and phosphate species; the osmotic pressure of CaAc2 and CaCl2 solutions is a small fraction of the experimental values for both force fields. Using the standard parameterization of Ca(2+) ions in the simulations of Ca(2+) -mediated DNA-DNA interactions leads to qualitatively wrong outcomes: both AMBER and CHARMM simulations suggest strong inter-DNA attraction whereas, in experiment, DNA molecules repel one another. The artificial attraction of Ca(2+) to DNA phosphate is strong enough to affect the direction of the electric field-driven translocation of DNA through a solid-state nanopore. To address these shortcomings of the standard Ca(2+) model, we introduce a custom model of a hydrated Ca(2+) ion and show that using our model brings the results of the above MD simulations in quantitative agreement with experiment. Our improved model of Ca(2+) can be readily applied to MD simulations of various biomolecular systems, including nucleic acids, proteins and lipid bilayer membranes. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 752-763, 2016. © 2016 Wiley Periodicals, Inc.
New generation of docking programs: Supercomputer validation of force fields and quantum-chemical methods for docking.

PubMed

Sulimov, Alexey V; Kutov, Danil C; Katkova, Ekaterina V; Ilin, Ivan S; Sulimov, Vladimir B

2017-11-01

Discovery of new inhibitors of the protein associated with a given disease is the initial and most important stage of the whole process of the rational development of new pharmaceutical substances. New inhibitors block the active site of the target protein and the disease is cured. Computer-aided molecular modeling can considerably increase effectiveness of new inhibitors development. Reliable predictions of the target protein inhibition by a small molecule, ligand, is defined by the accuracy of docking programs. Such programs position a ligand in the target protein and estimate the protein-ligand binding energy. Positioning accuracy of modern docking programs is satisfactory. However, the accuracy of binding energy calculations is too low to predict good inhibitors. For effective application of docking programs to new inhibitors development the accuracy of binding energy calculations should be higher than 1kcal/mol. Reasons of limited accuracy of modern docking programs are discussed. One of the most important aspects limiting this accuracy is imperfection of protein-ligand energy calculations. Results of supercomputer validation of several force fields and quantum-chemical methods for docking are presented. The validation was performed by quasi-docking as follows. First, the low energy minima spectra of 16 protein-ligand complexes were found by exhaustive minima search in the MMFF94 force field. Second, energies of the lowest 8192 minima are recalculated with CHARMM force field and PM6-D3H4X and PM7 quantum-chemical methods for each complex. The analysis of minima energies reveals the docking positioning accuracies of the PM7 and PM6-D3H4X quantum-chemical methods and the CHARMM force field are close to one another and they are better than the positioning accuracy of the MMFF94 force field. Copyright © 2017 Elsevier Inc. All rights reserved.
Simulation of carbohydrates, from molecular docking to dynamics in water.

PubMed

Sapay, Nicolas; Nurisso, Alessandra; Imberty, Anne

2013-01-01

Modeling of carbohydrates is particularly challenging because of the variety of structures resulting for the high number of monosaccharides and possible linkages and also because of their intrinsic flexibility. The development of carbohydrate parameters for molecular modeling is still an active field. Nowadays, main carbohydrates force fields are GLYCAM06, CHARMM36, and GROMOS 45A4. GLYCAM06 includes the largest choice of compounds and is compatible with the AMBER force fields and associated. Furthermore, AMBER includes tools for the implementation of new parameters. When looking at protein-carbohydrate interaction, the choice of the starting structure is of importance. Such complex can be sometimes obtained from the Protein Data Bank-although the stereochemistry of sugars may require some corrections. When no experimental data is available, molecular docking simulation is generally used to the obtain protein-carbohydrate complex coordinates. As molecular docking parameters are not specifically dedicated to carbohydrates, inaccuracies should be expected, especially for the docking of polysaccharides. This issue can be addressed at least partially by combining molecular docking with molecular dynamics simulation in water.
CHARMM-GUI Membrane Builder toward realistic biological membrane simulations.

PubMed

Wu, Emilia L; Cheng, Xi; Jo, Sunhwan; Rui, Huan; Song, Kevin C; Dávila-Contreras, Eder M; Qi, Yifei; Lee, Jumin; Monje-Galvan, Viviana; Venable, Richard M; Klauda, Jeffery B; Im, Wonpil

2014-10-15

CHARMM-GUI Membrane Builder, http://www.charmm-gui.org/input/membrane, is a web-based user interface designed to interactively build all-atom protein/membrane or membrane-only systems for molecular dynamics simulations through an automated optimized process. In this work, we describe the new features and major improvements in Membrane Builder that allow users to robustly build realistic biological membrane systems, including (1) addition of new lipid types, such as phosphoinositides, cardiolipin (CL), sphingolipids, bacterial lipids, and ergosterol, yielding more than 180 lipid types, (2) enhanced building procedure for lipid packing around protein, (3) reliable algorithm to detect lipid tail penetration to ring structures and protein surface, (4) distance-based algorithm for faster initial ion displacement, (5) CHARMM inputs for P21 image transformation, and (6) NAMD equilibration and production inputs. The robustness of these new features is illustrated by building and simulating a membrane model of the polar and septal regions of E. coli membrane, which contains five lipid types: CL lipids with two types of acyl chains and phosphatidylethanolamine lipids with three types of acyl chains. It is our hope that CHARMM-GUI Membrane Builder becomes a useful tool for simulation studies to better understand the structure and dynamics of proteins and lipids in realistic biological membrane environments. Copyright © 2014 Wiley Periodicals, Inc.
Reparametrization of Protein Force Field Nonbonded Interactions Guided by Osmotic Coefficient Measurements from Molecular Dynamics Simulations.

PubMed

Miller, Mark S; Lay, Wesley K; Li, Shuxiang; Hacker, William C; An, Jiadi; Ren, Jianlan; Elcock, Adrian H

2017-04-11

There is a small, but growing, body of literature describing the use of osmotic coefficient measurements to validate and reparametrize simulation force fields. Here we have investigated the ability of five very commonly used force field and water model combinations to reproduce the osmotic coefficients of seven neutral amino acids and five small molecules. The force fields tested include AMBER ff99SB-ILDN, CHARMM36, GROMOS54a7, and OPLS-AA, with the first of these tested in conjunction with the TIP3P and TIP4P-Ew water models. In general, for both the amino acids and the small molecules, the tested force fields produce computed osmotic coefficients that are lower than experiment; this is indicative of excessively favorable solute-solute interactions. The sole exception to this general trend is provided by GROMOS54a7 when applied to amino acids: in this case, the computed osmotic coefficients are consistently too high. Importantly, we show that all of the force fields tested can be made to accurately reproduce the experimental osmotic coefficients of the amino acids when minor modifications-some previously reported by others and some that are new to this study-are made to the van der Waals interactions of the charged terminal groups. Special care is required, however, when simulating Proline with a number of the force fields, and a hydroxyl-group specific modification is required in order to correct Serine and Threonine when simulated with AMBER ff99SB-ILDN. Interestingly, an alternative parametrization of the van der Waals interactions in the latter force field, proposed by the Nerenberg and Head-Gordon groups, is shown to immediately produce osmotic coefficients that are in excellent agreement with experiment. Overall, this study reinforces the idea that osmotic coefficient measurements can be used to identify general shortcomings in commonly used force fields' descriptions of solute-solute interactions and further demonstrates that modifications to van der Waals parameters provide a simple route to optimizing agreement with experiment.
Reparameterization of Protein Force Field Nonbonded Interactions Guided by Osmotic Coefficient Measurements from Molecular Dynamics Simulations

PubMed Central

Miller, Mark S.; Lay, Wesley K.; Li, Shuxiang; Hacker, William C.; An, Jiadi; Ren, Jianlan; Elcock, Adrian H.

2017-01-01

There is a small, but growing, body of literature describing the use of osmotic coefficient measurements to validate and reparameterize simulation force fields. Here we have investigated the ability of five very commonly used force field and water model combinations to reproduce the osmotic coefficients of seven neutral amino acids and five small molecules. The force fields tested include AMBER ff99SB-ILDN, CHARMM36, GROMOS54a7, and OPLS-AA, with the first of these tested in conjunction with the TIP3P and TIP4P-Ew water models. In general, for both the amino acids and the small molecules, the tested force fields produce computed osmotic coefficients that are lower than experiment; this is indicative of excessively favorable solute-solute interactions. The sole exception to this general trend is provided by GROMOS54a7 when applied to amino acids: in this case, the computed osmotic coefficients are consistently too high. Importantly, we show that all of the force fields tested can be made to accurately reproduce the experimental osmotic coefficients of the amino acids when minor modifications – some previously reported by others and some that are new to this study – are made to the van der Waals interactions of the charged terminal groups. Special care is required, however, when simulating Proline with a number of the force fields, and a hydroxyl-group specific modification is required in order to correct Serine and Threonine when simulated with AMBER ff99SB-ILDN. Interestingly, an alternative parameterization of the van der Waals interactions in the latter force field, proposed by the Nerenberg and Head-Gordon groups, is shown to immediately produce osmotic coefficients that are in excellent agreement with experiment. Overall, this study reinforces the idea that osmotic coefficient measurements can be used to identify general shortcomings in commonly used force fields’ descriptions of solute-solute interactions, and further demonstrates that modifications to van der Waals parameters provides a simple route to optimizing agreement with experiment. PMID:28296391
On the Helix Propensity in Generalized Born Solvent Descriptions of Modeling the Dark Proteome

PubMed Central

Olson, Mark A.

2017-01-01

Intrinsically disordered proteins that populate the so-called “Dark Proteome” offer challenging benchmarks of atomistic simulation methods to accurately model conformational transitions on a multidimensional energy landscape. This work explores the application of parallel tempering with implicit solvent models as a computational framework to capture the conformational ensemble of an intrinsically disordered peptide derived from the Ebola virus protein VP35. A recent X-ray crystallographic study reported a protein-peptide interface where the VP35 peptide underwent a folding transition from a disordered form to a helix-β-turn-helix topological fold upon molecular association with the Ebola protein NP. An assessment is provided of the accuracy of two generalized Born solvent models (GBMV2 and GBSW2) using the CHARMM force field and applied with temperature-based replica exchange dynamics to calculate the disorder propensity of the peptide and its probability density of states in a continuum solvent. A further comparison is presented of applying an explicit/implicit solvent hybrid replica exchange simulation of the peptide to determine the effect of modeling water interactions at the all-atom resolution. PMID:28197405
On the Helix Propensity in Generalized Born Solvent Descriptions of Modeling the Dark Proteome.

PubMed

Olson, Mark A

2017-01-01

Intrinsically disordered proteins that populate the so-called "Dark Proteome" offer challenging benchmarks of atomistic simulation methods to accurately model conformational transitions on a multidimensional energy landscape. This work explores the application of parallel tempering with implicit solvent models as a computational framework to capture the conformational ensemble of an intrinsically disordered peptide derived from the Ebola virus protein VP35. A recent X-ray crystallographic study reported a protein-peptide interface where the VP35 peptide underwent a folding transition from a disordered form to a helix-β-turn-helix topological fold upon molecular association with the Ebola protein NP. An assessment is provided of the accuracy of two generalized Born solvent models (GBMV2 and GBSW2) using the CHARMM force field and applied with temperature-based replica exchange dynamics to calculate the disorder propensity of the peptide and its probability density of states in a continuum solvent. A further comparison is presented of applying an explicit/implicit solvent hybrid replica exchange simulation of the peptide to determine the effect of modeling water interactions at the all-atom resolution.
Glycan Reader: Automated Sugar Identification and Simulation Preparation for Carbohydrates and Glycoproteins

PubMed Central

Jo, Sunhwan; Song, Kevin C.; Desaire, Heather; MacKerell, Alexander D.; Im, Wonpil

2011-01-01

Understanding how glycosylation affects protein structure, dynamics, and function is an emerging and challenging problem in biology. As a first step toward glycan modeling in the context of structural glycobiology, we have developed Glycan Reader and integrated it into the CHARMM-GUI, http://www.charmm-gui.org/input/glycan. Glycan Reader greatly simplifies the reading of PDB structure files containing glycans through (i) detection of carbohydrate molecules, (ii) automatic annotation of carbohydrates based on their three-dimensional structures, (iii) recognition of glycosidic linkages between carbohydrates as well as N-/O-glycosidic linkages to proteins, and (iv) generation of inputs for the biomolecular simulation program CHARMM with the proper glycosidic linkage setup. In addition, Glycan Reader is linked to other functional modules in CHARMM-GUI, allowing users to easily generate carbohydrate or glycoprotein molecular simulation systems in solution or membrane environments and visualize the electrostatic potential on glycoprotein surfaces. These tools are useful for studying the impact of glycosylation on protein structure and dynamics. PMID:21815173
Influence of various force fields in estimating the binding affinity of acetylcholinesterase inhibitors using fast pulling of ligand scheme

NASA Astrophysics Data System (ADS)

Tam, Nguyen Minh; Vu, Khanh B.; Vu, Van V.; Ngo, Son Tung

2018-06-01

Acetylcholinesterase (AChE) is considered as one of the most favored drug targets for Alzheimer's disease. The effects of different force fields (FFs) on ranking affinity of acetylcholinesterase inhibitors were obtained using the fast pulling of ligand (FPL) method in steered-molecular dynamics (SMD) simulations. GROMOS, AMBER, CHARMM, and OPLS-AA FFs were investigated in this work. The pulling work derived with GROMOS FF has the strongest correlation and smallest error compared with experimental binding affinity. Moreover, the CPU consumption in the calculations using GROMOS FF is the lowest, which could allow us to rank affinity of a large number of AChE ligands.
Charge Equilibration Force Fields for Lipid Environments: Applications to Fully Hydrated DPPC Bilayers and DMPC-Embedded Gramicidin A

PubMed Central

Davis, Joseph E.; Patel, Sandeep

2009-01-01

Polarizable force fields for lipid and solvent environments are used for molecular dynamics simulations of a fully hydrated dipalmitoylphosphatidylcholine (DPPC) bilayer and gramicidin A (gA) dimer embedded in a dimyristoylphosphatidylcholine (DMPC) bilayer. The lipid bilayer is modelled using the CHARMM charge equilibration (CHEQ) polarizable force field for lipids and the TIP4P-FQ force field to represent solvent. For the DPPC bilayer system, results are compared to the same system simulated using the nonpolarizable CHARMM27r (C27r) force field and TIP3P water. Calculated atomic and electron density profiles, headgroup orientations as measured by the phosphorus-nitrogen vector orientation, and deuterium order parameters are found to be consistent with previous simulations and with experiment. The CHEQ model exhibits greater water penetration into the bilayer interior, as demonstrated by the potential of mean force calculated from the water density profile. This is a result of the variation of the water molecular dipole from 2.55 D in the bulk to 1.88 D in the interior. We discuss this finding in the context of previous studies (both simulation and experiment) that have investigated the extent of penetration of water into DPPC bilayers. We also discuss the effects of including explicit polarization on the water dipole moment variation as a function of distance from the bilayer. We show distributions of atomic charges over the course of the simulation, since the CHEQ model allows the charges to fluctuate. We have calculated the interfacial dipole potential, which the CHEQ model predicts to be 0.95 V compared to 0.86 V as predicted by the C27r model. We also discuss dielectric permittivity profiles and the differences arising between the two models. We obtain bulk values of 72.77 for the CHEQ model (TIP4P-FQ water) and 91.22 for C27r (TIP3P), and values approaching unity in the membrane interior. Finally, we present results of simulations of gA embedded in a DMPC bilayer using the CHEQ model and discuss structural properties. PMID:19526999
Studying chemical reactions in biological systems with MBN Explorer: implementation of molecular mechanics with dynamical topology

NASA Astrophysics Data System (ADS)

Sushko, Gennady B.; Solov'yov, Ilia A.; Verkhovtsev, Alexey V.; Volkov, Sergey N.; Solov'yov, Andrey V.

2016-01-01

The concept of molecular mechanics force field has been widely accepted nowadays for studying various processes in biomolecular systems. In this paper, we suggest a modification for the standard CHARMM force field that permits simulations of systems with dynamically changing molecular topologies. The implementation of the modified force field was carried out in the popular program MBN Explorer, and, to support the development, we provide several illustrative case studies where dynamical topology is necessary. In particular, it is shown that the modified molecular mechanics force field can be applied for studying processes where rupture of chemical bonds plays an essential role, e.g., in irradiation- or collision-induced damage, and also in transformation and fragmentation processes involving biomolecular systems. Contribution to the Topical Issue "COST Action Nano-IBCT: Nano-scale Processes Behind Ion-Beam Cancer Therapy", edited by Andrey V. Solov'yov, Nigel Mason, Gustavo Garcia and Eugene Surdutovich.
Improved Force Fields for Peptide Nucleic Acids with Optimized Backbone Torsion Parameters.

PubMed

Jasiński, Maciej; Feig, Michael; Trylska, Joanna

2018-06-06

Peptide nucleic acids are promising nucleic acid analogs for antisense therapies as they can form stable duplex and triplex structures with DNA and RNA. Computational studies of PNA-containing duplexes and triplexes are an important component for guiding their design, yet existing force fields have not been well validated and parametrized with modern computational capabilities. We present updated CHARMM and Amber force fields for PNA that greatly improve the stability of simulated PNA-containing duplexes and triplexes in comparison with experimental structures and allow such systems to be studied on microsecond time scales. The force field modifications focus on reparametrized PNA backbone torsion angles to match high-level quantum mechanics reference energies for a model compound. The microsecond simulations of PNA-PNA, PNA-DNA, PNA-RNA, and PNA-DNA-PNA complexes also allowed a comprehensive analysis of hydration and ion interactions with such systems.
Evaluating Force Fields for the Computational Prediction of Ionized Arginine and Lysine Side-Chains Partitioning into Lipid Bilayers and Octanol.

PubMed

Sun, Delin; Forsman, Jan; Woodward, Clifford E

2015-04-14

Abundant peptides and proteins containing arginine (Arg) and lysine (Lys) amino acids can apparently permeate cell membranes with ease. However, the mechanisms by which these peptides and proteins succeed in traversing the free energy barrier imposed by cell membranes remain largely unestablished. Precise thermodynamic studies (both theoretical and experimental) on the interactions of Arg and Lys residues with model lipid bilayers can provide valuable clues to the efficacy of these cationic peptides and proteins. We have carried out molecular dynamics simulations to calculate the interactions of ionized Arg and Lys side-chains with the zwitterionic 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayer for 10 widely used lipid/protein force fields: CHARMM36/CHARMM36, SLIPID/AMBER99SB-ILDN, OPLS-AA/OPLS-AA, Berger/OPLS-AA, Berger/GROMOS87, Berger/GROMOS53A6, GROMOS53A6/GROMOS53A6, nonpolarizable MARTINI, polarizable MARTINI, and BMW MARTINI. We performed umbrella sampling simulations to obtain the potential of mean force for Arg and Lys side-chains partitioning from water to the bilayer interior. We found significant differences between the force fields, both for the interactions between side-chains and bilayer surface, as well as the free energy cost for placing the side-chain at the center of the bilayer. These simulation results were compared with the Wimley-White interfacial scale. We also calculated the free energy cost for transferring ionized Arg and Lys side-chains from water to both dry and wet octanol. Our simulations reveal rapid diffusion of water molecules into octanol whereby the equilibrium mole fraction of water in the wet octanol phase was ∼25%. Surprisingly, our free energy calculations found that the high water content in wet octanol lowered the water-to-octanol partitioning free energies for cationic residues by only 0.6 to 0.7 kcal/mol.
Binding preference of carbon nanotube over proline-rich motif ligand on SH3-domain: a comparison with different force fields.

PubMed

Shi, Biyun; Zuo, Guanghong; Xiu, Peng; Zhou, Ruhong

2013-04-04

With the widespread applications of nanomaterials such as carbon nanotubes, there is a growing concern on the biosafety of these engineered nanoparticles, in particular their interactions with proteins. In molecular simulations of nanoparticle-protein interactions, the choice of empirical parameters (force fields) plays a decisive role, and thus is of great importance and should be examined carefully before wider applications. Here we compare three commonly used force fields, CHARMM, OPLSAA, and AMBER in study of the competitive binding of a single wall carbon nanotube (SWCNT) with a native proline-rich motif (PRM) ligand on its target protein SH3 domain, a ubiquitous protein-protein interaction mediator involved in signaling and regulatory pathways. We find that the SWCNT displays a general preference over the PRM in binding with SH3 domain in all the three force fields examined, although the degree of preference can be somewhat different, with the AMBER force field showing the highest preference. The SWCNT prevents the ligand from reaching its native binding pocket by (i) occupying the binding pocket directly, and (ii) binding with the ligand itself and then being trapped together onto some off-sites. The π-π stacking interactions between the SWCNT and aromatic residues are found to play a significant role in its binding to the SH3 domain in all the three force fields. Further analyses show that even the SWCNT-ligand binding can also be relatively more stable than the native ligand-protein binding, indicating a serious potential disruption to the protein SH3 function.
Electrostatic Solvation Free Energy of Amino Acid Side Chain Analogs: Implications for the Validity of Electrostatic Linear Response in Water

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

Lin, Bin; Pettitt, Bernard M.

Electrostatic free energies of solvation for 15 neutral amino acid side chain analogs are computed. We compare three methods of varying computational complexity and accuracy for three force fields: free energy simulations, Poisson-Boltzmann (PB), and linear response approximation (LRA) using AMBER, CHARMM, and OPLSAA force fields. We find that deviations from simulation start at low charges for solutes. The approximate PB and LRA produce an overestimation of electrostatic solvation free energies for most of molecules studied here. These deviations are remarkably systematic. The variations among force fields are almost as large as the variations found among methods. Our study confirmsmore » that success of the approximate methods for electrostatic solvation free energies comes from their ability to evaluate free energy differences accurately.« less

Molecular Dynamics Study of the Structure, Flexibility, and Hydrophilicity of PETIM Dendrimers: A Comparison with PAMAM Dendrimers.

PubMed

Kanchi, Subbarao; Suresh, Gorle; Priyakumar, U Deva; Ayappa, K G; Maiti, Prabal K

2015-10-15

A new class of dendrimers, the poly(propyl ether imine) (PETIM) dendrimer, has been shown to be a novel hyperbranched polymer having potential applications as a drug delivery vehicle. Structure and dynamics of the amine terminated PETIM dendrimer and their changes with respect to the dendrimer generation are poorly understood. Since most drugs are hydrophobic in nature, the extent of hydrophobicity of the dendrimer core is related to its drug encapsulation and retention efficacy. In this study, we carry out fully atomistic molecular dynamics (MD) simulations to characterize the structure of PETIM (G2-G6) dendrimers in salt solution as a function of dendrimer generation at different protonation levels. Structural properties such as radius of gyration (Rg), radial density distribution, aspect ratio, and asphericity are calculated. In order to assess the hydrophilicity of the dendrimer, we compute the number of bound water molecules in the interior of dendrimer as well as the number of dendrimer-water hydrogen bonds. We conclude that PETIM dendrimers have relatively greater hydrophobicity and flexibility when compared with their extensively investigated PAMAM counterparts. Hence PETIM dendrimers are expected to have stronger interactions with lipid membranes as well as improved drug encapsulation and retention properties when compared with PAMAM dendrimers. We compute the root-mean-square fluctuation of dendrimers as well as their entropy to quantify the flexibility of the dendrimer. Finally we note that structural and solvation properties computed using force field parameters derived based on the CHARMM general purpose force field were in good quantitative agreement with those obtained using the generalized Amber force field (GAFF).
Fixed-Charge Atomistic Force Fields for Molecular Dynamics Simulations in the Condensed Phase: An Overview.

PubMed

Riniker, Sereina

2018-03-26

In molecular dynamics or Monte Carlo simulations, the interactions between the particles (atoms) in the system are described by a so-called force field. The empirical functional form of classical fixed-charge force fields dates back to 1969 and remains essentially unchanged. In a fixed-charge force field, the polarization is not modeled explicitly, i.e. the effective partial charges do not change depending on conformation and environment. This simplification allows, however, a dramatic reduction in computational cost compared to polarizable force fields and in particular quantum-chemical modeling. The past decades have shown that simulations employing carefully parametrized fixed-charge force fields can provide useful insights into biological and chemical questions. This overview focuses on the four major force-field families, i.e. AMBER, CHARMM, GROMOS, and OPLS, which are based on the same classical functional form and are continuously improved to the present day. The overview is aimed at readers entering the field of (bio)molecular simulations. More experienced users may find the comparison and historical development of the force-field families interesting.
A Simplified Model of Local Structure in Aqueous Proline Amino Acid Revealed by First-Principles Molecular Dynamics Simulations

PubMed Central

Troitzsch, Raphael Z.; Tulip, Paul R.; Crain, Jason; Martyna, Glenn J.

2008-01-01

Aqueous proline solutions are deceptively simple as they can take on complex roles such as protein chaperones, cryoprotectants, and hydrotropic agents in biological processes. Here, a molecular level picture of proline/water mixtures is developed. Car-Parrinello ab initio molecular dynamics (CPAIMD) simulations of aqueous proline amino acid at the B-LYP level of theory, performed using IBM's Blue Gene/L supercomputer and massively parallel software, reveal hydrogen-bonding propensities that are at odds with the predictions of the CHARMM22 empirical force field but are in better agreement with results of recent neutron diffraction experiments. In general, the CPAIMD (B-LYP) simulations predict a simplified structural model of proline/water mixtures consisting of fewer distinct local motifs. Comparisons of simulation results to experiment are made by direct evaluation of the neutron static structure factor S(Q) from CPAIMD (B-LYP) trajectories as well as to the results of the empirical potential structure refinement reverse Monte Carlo procedure applied to the neutron data. PMID:18790850
A simplified model of local structure in aqueous proline amino acid revealed by first-principles molecular dynamics simulations.

PubMed

Troitzsch, Raphael Z; Tulip, Paul R; Crain, Jason; Martyna, Glenn J

2008-12-01

Aqueous proline solutions are deceptively simple as they can take on complex roles such as protein chaperones, cryoprotectants, and hydrotropic agents in biological processes. Here, a molecular level picture of proline/water mixtures is developed. Car-Parrinello ab initio molecular dynamics (CPAIMD) simulations of aqueous proline amino acid at the B-LYP level of theory, performed using IBM's Blue Gene/L supercomputer and massively parallel software, reveal hydrogen-bonding propensities that are at odds with the predictions of the CHARMM22 empirical force field but are in better agreement with results of recent neutron diffraction experiments. In general, the CPAIMD (B-LYP) simulations predict a simplified structural model of proline/water mixtures consisting of fewer distinct local motifs. Comparisons of simulation results to experiment are made by direct evaluation of the neutron static structure factor S(Q) from CPAIMD (B-LYP) trajectories as well as to the results of the empirical potential structure refinement reverse Monte Carlo procedure applied to the neutron data.
MDAnalysis: a toolkit for the analysis of molecular dynamics simulations.

PubMed

Michaud-Agrawal, Naveen; Denning, Elizabeth J; Woolf, Thomas B; Beckstein, Oliver

2011-07-30

MDAnalysis is an object-oriented library for structural and temporal analysis of molecular dynamics (MD) simulation trajectories and individual protein structures. It is written in the Python language with some performance-critical code in C. It uses the powerful NumPy package to expose trajectory data as fast and efficient NumPy arrays. It has been tested on systems of millions of particles. Many common file formats of simulation packages including CHARMM, Gromacs, Amber, and NAMD and the Protein Data Bank format can be read and written. Atoms can be selected with a syntax similar to CHARMM's powerful selection commands. MDAnalysis enables both novice and experienced programmers to rapidly write their own analytical tools and access data stored in trajectories in an easily accessible manner that facilitates interactive explorative analysis. MDAnalysis has been tested on and works for most Unix-based platforms such as Linux and Mac OS X. It is freely available under the GNU General Public License from http://mdanalysis.googlecode.com. Copyright © 2011 Wiley Periodicals, Inc.
New Distributed Multipole Methods for Accurate Electrostatics for Large-Scale Biomolecular Simultations

NASA Astrophysics Data System (ADS)

Sagui, Celeste

2006-03-01

An accurate and numerically efficient treatment of electrostatics is essential for biomolecular simulations, as this stabilizes much of the delicate 3-d structure associated with biomolecules. Currently, force fields such as AMBER and CHARMM assign ``partial charges'' to every atom in a simulation in order to model the interatomic electrostatic forces, so that the calculation of the electrostatics rapidly becomes the computational bottleneck in large-scale simulations. There are two main issues associated with the current treatment of classical electrostatics: (i) how does one eliminate the artifacts associated with the point-charges (e.g., the underdetermined nature of the current RESP fitting procedure for large, flexible molecules) used in the force fields in a physically meaningful way? (ii) how does one efficiently simulate the very costly long-range electrostatic interactions? Recently, we have dealt with both of these challenges as follows. In order to improve the description of the molecular electrostatic potentials (MEPs), a new distributed multipole analysis based on localized functions -- Wannier, Boys, and Edminston-Ruedenberg -- was introduced, which allows for a first principles calculation of the partial charges and multipoles. Through a suitable generalization of the particle mesh Ewald (PME) and multigrid method, one can treat electrostatic multipoles all the way to hexadecapoles all without prohibitive extra costs. The importance of these methods for large-scale simulations will be discussed, and examplified by simulations from polarizable DNA models.
The Distributed Diagonal Force Decomposition Method for Parallelizing Molecular Dynamics Simulations

PubMed Central

Boršnik, Urban; Miller, Benjamin T.; Brooks, Bernard R.; Janežič, Dušanka

2011-01-01

Parallelization is an effective way to reduce the computational time needed for molecular dynamics simulations. We describe a new parallelization method, the distributed-diagonal force decomposition method, with which we extend and improve the existing force decomposition methods. Our new method requires less data communication during molecular dynamics simulations than replicated data and current force decomposition methods, increasing the parallel efficiency. It also dynamically load-balances the processors' computational load throughout the simulation. The method is readily implemented in existing molecular dynamics codes and it has been incorporated into the CHARMM program, allowing its immediate use in conjunction with the many molecular dynamics simulation techniques that are already present in the program. We also present the design of the Force Decomposition Machine, a cluster of personal computers and networks that is tailored to running molecular dynamics simulations using the distributed diagonal force decomposition method. The design is expandable and provides various degrees of fault resilience. This approach is easily adaptable to computers with Graphics Processing Units because it is independent of the processor type being used. PMID:21793007
Electrostatics of cysteine residues in proteins: Parameterization and validation of a simple model

PubMed Central

Salsbury, Freddie R.; Poole, Leslie B.; Fetrow, Jacquelyn S.

2013-01-01

One of the most popular and simple models for the calculation of pKas from a protein structure is the semi-macroscopic electrostatic model MEAD. This model requires empirical parameters for each residue to calculate pKas. Analysis of current, widely used empirical parameters for cysteine residues showed that they did not reproduce expected cysteine pKas; thus, we set out to identify parameters consistent with the CHARMM27 force field that capture both the behavior of typical cysteines in proteins and the behavior of cysteines which have perturbed pKas. The new parameters were validated in three ways: (1) calculation across a large set of typical cysteines in proteins (where the calculations are expected to reproduce expected ensemble behavior); (2) calculation across a set of perturbed cysteines in proteins (where the calculations are expected to reproduce the shifted ensemble behavior); and (3) comparison to experimentally determined pKa values (where the calculation should reproduce the pKa within experimental error). Both the general behavior of cysteines in proteins and the perturbed pKa in some proteins can be predicted reasonably well using the newly determined empirical parameters within the MEAD model for protein electrostatics. This study provides the first general analysis of the electrostatics of cysteines in proteins, with specific attention paid to capturing both the behavior of typical cysteines in a protein and the behavior of cysteines whose pKa should be shifted, and validation of force field parameters for cysteine residues. PMID:22777874
PBEQ-Solver for online visualization of electrostatic potential of biomolecules.

PubMed

Jo, Sunhwan; Vargyas, Miklos; Vasko-Szedlar, Judit; Roux, Benoît; Im, Wonpil

2008-07-01

PBEQ-Solver provides a web-based graphical user interface to read biomolecular structures, solve the Poisson-Boltzmann (PB) equations and interactively visualize the electrostatic potential. PBEQ-Solver calculates (i) electrostatic potential and solvation free energy, (ii) protein-protein (DNA or RNA) electrostatic interaction energy and (iii) pKa of a selected titratable residue. All the calculations can be performed in both aqueous solvent and membrane environments (with a cylindrical pore in the case of membrane). PBEQ-Solver uses the PBEQ module in the biomolecular simulation program CHARMM to solve the finite-difference PB equation of molecules specified by users. Users can interactively inspect the calculated electrostatic potential on the solvent-accessible surface as well as iso-electrostatic potential contours using a novel online visualization tool based on MarvinSpace molecular visualization software, a Java applet integrated within CHARMM-GUI (http://www.charmm-gui.org). To reduce the computational time on the server, and to increase the efficiency in visualization, all the PB calculations are performed with coarse grid spacing (1.5 A before and 1 A after focusing). PBEQ-Solver suggests various physical parameters for PB calculations and users can modify them if necessary. PBEQ-Solver is available at http://www.charmm-gui.org/input/pbeqsolver.
Properties of Organic Liquids when Simulated with Long-Range Lennard-Jones Interactions.

PubMed

Fischer, Nina M; van Maaren, Paul J; Ditz, Jonas C; Yildirim, Ahmet; van der Spoel, David

2015-07-14

In order to increase the accuracy of classical computer simulations, existing methodologies may need to be adapted. Hitherto, most force fields employ a truncated potential function to model van der Waals interactions, sometimes augmented with an analytical correction. Although such corrections are accurate for homogeneous systems with a long cutoff, they should not be used in inherently inhomogeneous systems such as biomolecular and interface systems. For such cases, a variant of the particle mesh Ewald algorithm (Lennard-Jones PME) was already proposed 20 years ago (Essmann et al. J. Chem. Phys. 1995, 103, 8577-8593), but it was implemented only recently (Wennberg et al. J. Chem. Theory Comput. 2013, 9, 3527-3537) in a major simulation code (GROMACS). The availability of this method allows surface tensions of liquids as well as bulk properties to be established, such as density and enthalpy of vaporization, without approximations due to truncation. Here, we report on simulations of ≈150 liquids (taken from a force field benchmark: Caleman et al. J. Chem. Theory Comput. 2012, 8, 61-74) using three different force fields and compare simulations with and without explicit long-range van der Waals interactions. We find that the density and enthalpy of vaporization increase for most liquids using the generalized Amber force field (GAFF, Wang et al. J. Comput. Chem. 2004, 25, 1157-1174) and the Charmm generalized force field (CGenFF, Vanommeslaeghe et al. J. Comput. Chem. 2010, 31, 671-690) but less so for OPLS/AA (Jorgensen and Tirado-Rives, Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 6665-6670), which was parametrized with an analytical correction to the van der Waals potential. The surface tension increases by ≈10(-2) N/m for all force fields. These results suggest that van der Waals attractions in force fields are too strong, in particular for the GAFF and CGenFF. In addition to the simulation results, we introduce a new version of a web server, http://virtualchemistry.org, aimed at facilitating sharing and reuse of input files for molecular simulations.
Force Field for Peptides and Proteins based on the Classical Drude Oscillator

PubMed Central

Lopes, Pedro E.M.; Huang, Jing; Shim, Jihyun; Luo, Yun; Li, Hui; Roux, Benoît; MacKerell, Alexander D.

2013-01-01

Presented is a polarizable force field based on a classical Drude oscillator framework, currently implemented in the programs CHARMM and NAMD, for modeling and molecular dynamics (MD) simulation studies of peptides and proteins. Building upon parameters for model compounds representative of the functional groups in proteins, the development of the force field focused on the optimization of the parameters for the polypeptide backbone and the connectivity between the backbone and side chains. Optimization of the backbone electrostatic parameters targeted quantum mechanical conformational energies, interactions with water, molecular dipole moments and polarizabilities and experimental condensed phase data for short polypeptides such as (Ala)5. Additional optimization of the backbone φ, ψ conformational preferences included adjustments of the tabulated two-dimensional spline function through the CMAP term. Validation of the model included simulations of a collection of peptides and proteins. This 1st generation polarizable model is shown to maintain the folded state of the studied systems on the 100 ns timescale in explicit solvent MD simulations. The Drude model typically yields larger RMS differences as compared to the additive CHARMM36 force field (C36) and shows additional flexibility as compared to the additive model. Comparison with NMR chemical shift data shows a small degradation of the polarizable model with respect to the additive, though the level of agreement may be considered satisfactory, while for residues shown to have significantly underestimated S2 order parameters in the additive model, improvements are calculated with the polarizable model. Analysis of dipole moments associated with the peptide backbone and tryptophan side chains show the Drude model to have significantly larger values than those present in C36, with the dipole moments of the peptide backbone enhanced to a greater extent in sheets versus helices and the dipoles of individual moieties observed to undergo significant variations during the MD simulations. Although there are still some limitations, the presented model, termed Drude-2013, is anticipated to yield a molecular picture of peptide and protein structure and function that will be of increased physical validity and internal consistency in a computationally accessible fashion. PMID:24459460
Improved side-chain torsion potentials for the Amber ff99SB protein force field

PubMed Central

Lindorff-Larsen, Kresten; Piana, Stefano; Palmo, Kim; Maragakis, Paul; Klepeis, John L; Dror, Ron O; Shaw, David E

2010-01-01

Recent advances in hardware and software have enabled increasingly long molecular dynamics (MD) simulations of biomolecules, exposing certain limitations in the accuracy of the force fields used for such simulations and spurring efforts to refine these force fields. Recent modifications to the Amber and CHARMM protein force fields, for example, have improved the backbone torsion potentials, remedying deficiencies in earlier versions. Here, we further advance simulation accuracy by improving the amino acid side-chain torsion potentials of the Amber ff99SB force field. First, we used simulations of model alpha-helical systems to identify the four residue types whose rotamer distribution differed the most from expectations based on Protein Data Bank statistics. Second, we optimized the side-chain torsion potentials of these residues to match new, high-level quantum-mechanical calculations. Finally, we used microsecond-timescale MD simulations in explicit solvent to validate the resulting force field against a large set of experimental NMR measurements that directly probe side-chain conformations. The new force field, which we have termed Amber ff99SB-ILDN, exhibits considerably better agreement with the NMR data. Proteins 2010. © 2010 Wiley-Liss, Inc. PMID:20408171
Prediction of Protein-Peptide Interactions: Application of the XPairIT to Anthrax Lethal Factor and Substrates

DTIC Science & Technology

2013-09-01

hydrogen bonds in Tyrosine-containing peptides. Dalkas et al[7] used docking and molecular dynamics simulations to study a variety of MAPKK-based... simulated using NAMD molecular dynamics and the CHARMM[20] forcefield at 300K and employing the Generalized Born Implicit Solvent (GBIS[21]) with the...which were reported in Section 2. Specifically, after a ~10ns molecular dynamics simulation in TIP3 explicit water, significant motion of domains III
Electrostatics of cysteine residues in proteins: parameterization and validation of a simple model.

PubMed

Salsbury, Freddie R; Poole, Leslie B; Fetrow, Jacquelyn S

2012-11-01

One of the most popular and simple models for the calculation of pK(a) s from a protein structure is the semi-macroscopic electrostatic model MEAD. This model requires empirical parameters for each residue to calculate pK(a) s. Analysis of current, widely used empirical parameters for cysteine residues showed that they did not reproduce expected cysteine pK(a) s; thus, we set out to identify parameters consistent with the CHARMM27 force field that capture both the behavior of typical cysteines in proteins and the behavior of cysteines which have perturbed pK(a) s. The new parameters were validated in three ways: (1) calculation across a large set of typical cysteines in proteins (where the calculations are expected to reproduce expected ensemble behavior); (2) calculation across a set of perturbed cysteines in proteins (where the calculations are expected to reproduce the shifted ensemble behavior); and (3) comparison to experimentally determined pK(a) values (where the calculation should reproduce the pK(a) within experimental error). Both the general behavior of cysteines in proteins and the perturbed pK(a) in some proteins can be predicted reasonably well using the newly determined empirical parameters within the MEAD model for protein electrostatics. This study provides the first general analysis of the electrostatics of cysteines in proteins, with specific attention paid to capturing both the behavior of typical cysteines in a protein and the behavior of cysteines whose pK(a) should be shifted, and validation of force field parameters for cysteine residues. Copyright © 2012 Wiley Periodicals, Inc.
Absolute binding free energy calculations of CBClip host–guest systems in the SAMPL5 blind challenge

PubMed Central

Tofoleanu, Florentina; Pickard, Frank C.; König, Gerhard; Huang, Jing; Damjanović, Ana; Baek, Minkyung; Seok, Chaok; Brooks, Bernard R.

2016-01-01

Herein, we report the absolute binding free energy calculations of CBClip complexes in the SAMPL5 blind challenge. Initial conformations of CBClip complexes were obtained using docking and molecular dynamics simulations. Free energy calculations were performed using thermodynamic integration (TI) with soft-core potentials and Bennett’s acceptance ratio (BAR) method based on a serial insertion scheme. We compared the results obtained with TI simulations with soft-core potentials and Hamiltonian replica exchange simulations with the serial insertion method combined with the BAR method. The results show that the difference between the two methods can be mainly attributed to the van der Waals free energies, suggesting that either the simulations used for TI or the simulations used for BAR, or both are not fully converged and the two sets of simulations may have sampled difference phase space regions. The penalty scores of force field parameters of the 10 guest molecules provided by CHARMM Generalized Force Field can be an indicator of the accuracy of binding free energy calculations. Among our submissions, the combination of docking and TI performed best, which yielded the root mean square deviation of 2.94 kcal/mol and an average unsigned error of 3.41 kcal/mol for the ten guest molecules. These values were best overall among all participants. However, our submissions had little correlation with experiments. PMID:27677749
Quantum Effects in Cation Interactions with First and Second Coordination Shell Ligands in Metalloproteins

PubMed Central

2015-01-01

Despite decades of investigations, the principal mechanisms responsible for the high affinity and specificity of proteins for key physiological cations K+, Na+, and Ca2+ remain a hotly debated topic. At the core of the debate is an apparent need (or lack thereof) for an accurate description of the electrostatic response of the charge distribution in a protein to the binding of an ion. These effects range from partial electronic polarization of the directly ligating atoms to long-range effects related to partial charge transfer and electronic delocalization effects. While accurate modeling of cation recognition by metalloproteins warrants the use of quantum-mechanics (QM) calculations, the most popular approximations used in major biomolecular simulation packages rely on the implicit modeling of electronic polarization effects. That is, high-level QM computations for ion binding to proteins are desirable, but they are often unfeasible, because of the large size of the reactive-site models and the need to sample conformational space exhaustively at finite temperature. Several solutions to this challenge have been proposed in the field, ranging from the recently developed Drude polarizable force-field for simulations of metalloproteins to approximate tight-binding density functional theory (DFTB). To delineate the usefulness of different approximations, we examined the accuracy of three recent and commonly used theoretical models and numerical algorithms, namely, CHARMM C36, the latest developed Drude polarizable force fields, and DFTB3 with the latest 3OB parameters. We performed MD simulations for 30 cation-selective proteins with high-resolution X-ray structures to create ensembles of structures for analysis with different levels of theory, e.g., additive and polarizable force fields, DFTB3, and DFT. The results from DFT computations were used to benchmark CHARMM C36, Drude, and DFTB3 performance. The explicit modeling of quantum effects unveils the key electrostatic properties of the protein sites and the importance of specific ion-protein interactions. One of the most interesting findings is that secondary coordination shells of proteins are noticeably perturbed in a cation-dependent manner, showing significant delocalization and long-range effects of charge transfer and polarization upon binding Ca2+. PMID:26574284
Mechanical properties of lipid bilayers from molecular dynamics simulation

PubMed Central

Venable, Richard M.; Brown, Frank L.H.; Pastor, Richard W.

2015-01-01

Lipid areas (Aℓ), bilayer area compressibilities (KA), bilayer bending constants (KC), and monolayer spontaneous curvatures (c0) from simulations using the CHARMM36 force field are reported for 12 representative homogenous lipid bilayers. Aℓ (or their surrogate, the average deuterium order parameter in the “plateau region” of the chain) agree very well with experiment, as do the KA. Simulated KC are in near quantitative agreement with vesicle flicker experiments, but are somewhat larger than KC from x-ray, pipette aspiration, and neutron spin echo for saturated lipids. Spontaneous curvatures of bilayer leaflets from the simulations are approximately 30% smaller than experimental values of monolayers in the inverse hexagonal phase. PMID:26238099
Application of molecular simulation to investigate chrome(III)-crosslinked collagen problems

NASA Astrophysics Data System (ADS)

Ding, Yun-Qiao; Chen, Cheng-Lung; Gu, Qi-Rui; Liao, Jun-Min; Chuang, Po-Hsiang

2014-04-01

Molecular dynamics simulation with a modified CHARMM (Chemistry at Harvard Macromolecular Mechanics) force field was carried out to investigate the properties of chrome-tanned collagen in comparison with chrome-free collagen under hydrated and dehydrated conditions. An attempt has been made to explain the microcosmic origins of the various properties of the chromium(III)-crosslinked collagen. The present simulation describes the clear crosslinking topology of polychromiums to peptide chains, identifies the linking site and the capacity of the linkage, explains why the efficiency is not 100% in a practical tanning process and provides a new viewpoint on the crosslinking of the polychromium with the side chains of the collagen.
Force Field Benchmark of Organic Liquids: Density, Enthalpy of Vaporization, Heat Capacities, Surface Tension, Isothermal Compressibility, Volumetric Expansion Coefficient, and Dielectric Constant.

PubMed

Caleman, Carl; van Maaren, Paul J; Hong, Minyan; Hub, Jochen S; Costa, Luciano T; van der Spoel, David

2012-01-10

The chemical composition of small organic molecules is often very similar to amino acid side chains or the bases in nucleic acids, and hence there is no a priori reason why a molecular mechanics force field could not describe both organic liquids and biomolecules with a single parameter set. Here, we devise a benchmark for force fields in order to test the ability of existing force fields to reproduce some key properties of organic liquids, namely, the density, enthalpy of vaporization, the surface tension, the heat capacity at constant volume and pressure, the isothermal compressibility, the volumetric expansion coefficient, and the static dielectric constant. Well over 1200 experimental measurements were used for comparison to the simulations of 146 organic liquids. Novel polynomial interpolations of the dielectric constant (32 molecules), heat capacity at constant pressure (three molecules), and the isothermal compressibility (53 molecules) as a function of the temperature have been made, based on experimental data, in order to be able to compare simulation results to them. To compute the heat capacities, we applied the two phase thermodynamics method (Lin et al. J. Chem. Phys.2003, 119, 11792), which allows one to compute thermodynamic properties on the basis of the density of states as derived from the velocity autocorrelation function. The method is implemented in a new utility within the GROMACS molecular simulation package, named g_dos, and a detailed exposé of the underlying equations is presented. The purpose of this work is to establish the state of the art of two popular force fields, OPLS/AA (all-atom optimized potential for liquid simulation) and GAFF (generalized Amber force field), to find common bottlenecks, i.e., particularly difficult molecules, and to serve as a reference point for future force field development. To make for a fair playing field, all molecules were evaluated with the same parameter settings, such as thermostats and barostats, treatment of electrostatic interactions, and system size (1000 molecules). The densities and enthalpy of vaporization from an independent data set based on simulations using the CHARMM General Force Field (CGenFF) presented by Vanommeslaeghe et al. (J. Comput. Chem.2010, 31, 671) are included for comparison. We find that, overall, the OPLS/AA force field performs somewhat better than GAFF, but there are significant issues with reproduction of the surface tension and dielectric constants for both force fields.
Force Field Benchmark of Organic Liquids: Density, Enthalpy of Vaporization, Heat Capacities, Surface Tension, Isothermal Compressibility, Volumetric Expansion Coefficient, and Dielectric Constant

PubMed Central

2011-01-01

The chemical composition of small organic molecules is often very similar to amino acid side chains or the bases in nucleic acids, and hence there is no a priori reason why a molecular mechanics force field could not describe both organic liquids and biomolecules with a single parameter set. Here, we devise a benchmark for force fields in order to test the ability of existing force fields to reproduce some key properties of organic liquids, namely, the density, enthalpy of vaporization, the surface tension, the heat capacity at constant volume and pressure, the isothermal compressibility, the volumetric expansion coefficient, and the static dielectric constant. Well over 1200 experimental measurements were used for comparison to the simulations of 146 organic liquids. Novel polynomial interpolations of the dielectric constant (32 molecules), heat capacity at constant pressure (three molecules), and the isothermal compressibility (53 molecules) as a function of the temperature have been made, based on experimental data, in order to be able to compare simulation results to them. To compute the heat capacities, we applied the two phase thermodynamics method (Lin et al. J. Chem. Phys.2003, 119, 11792), which allows one to compute thermodynamic properties on the basis of the density of states as derived from the velocity autocorrelation function. The method is implemented in a new utility within the GROMACS molecular simulation package, named g_dos, and a detailed exposé of the underlying equations is presented. The purpose of this work is to establish the state of the art of two popular force fields, OPLS/AA (all-atom optimized potential for liquid simulation) and GAFF (generalized Amber force field), to find common bottlenecks, i.e., particularly difficult molecules, and to serve as a reference point for future force field development. To make for a fair playing field, all molecules were evaluated with the same parameter settings, such as thermostats and barostats, treatment of electrostatic interactions, and system size (1000 molecules). The densities and enthalpy of vaporization from an independent data set based on simulations using the CHARMM General Force Field (CGenFF) presented by Vanommeslaeghe et al. (J. Comput. Chem.2010, 31, 671) are included for comparison. We find that, overall, the OPLS/AA force field performs somewhat better than GAFF, but there are significant issues with reproduction of the surface tension and dielectric constants for both force fields. PMID:22241968

Modeling the mechanism of CLN025 beta-hairpin formation

NASA Astrophysics Data System (ADS)

McKiernan, Keri A.; Husic, Brooke E.; Pande, Vijay S.

2017-09-01

Beta-hairpins are substructures found in proteins that can lend insight into more complex systems. Furthermore, the folding of beta-hairpins is a valuable test case for benchmarking experimental and theoretical methods. Here, we simulate the folding of CLN025, a miniprotein with a beta-hairpin structure, at its experimental melting temperature using a range of state-of-the-art protein force fields. We construct Markov state models in order to examine the thermodynamics, kinetics, mechanism, and rate-determining step of folding. Mechanistically, we find the folding process is rate-limited by the formation of the turn region hydrogen bonds, which occurs following the downhill hydrophobic collapse of the extended denatured protein. These results are presented in the context of established and contradictory theories of the beta-hairpin folding process. Furthermore, our analysis suggests that the AMBER-FB15 force field, at this temperature, best describes the characteristics of the full experimental CLN025 conformational ensemble, while the AMBER ff99SB-ILDN and CHARMM22* force fields display a tendency to overstabilize the native state.
Thermal nanostructure: An order parameter multiscale ensemble approach

NASA Astrophysics Data System (ADS)

Cheluvaraja, S.; Ortoleva, P.

2010-02-01

Deductive all-atom multiscale techniques imply that many nanosystems can be understood in terms of the slow dynamics of order parameters that coevolve with the quasiequilibrium probability density for rapidly fluctuating atomic configurations. The result of this multiscale analysis is a set of stochastic equations for the order parameters whose dynamics is driven by thermal-average forces. We present an efficient algorithm for sampling atomistic configurations in viruses and other supramillion atom nanosystems. This algorithm allows for sampling of a wide range of configurations without creating an excess of high-energy, improbable ones. It is implemented and used to calculate thermal-average forces. These forces are then used to search the free-energy landscape of a nanosystem for deep minima. The methodology is applied to thermal structures of Cowpea chlorotic mottle virus capsid. The method has wide applicability to other nanosystems whose properties are described by the CHARMM or other interatomic force field. Our implementation, denoted SIMNANOWORLD™, achieves calibration-free nanosystem modeling. Essential atomic-scale detail is preserved via a quasiequilibrium probability density while overall character is provided via predicted values of order parameters. Applications from virology to the computer-aided design of nanocapsules for delivery of therapeutic agents and of vaccines for nonenveloped viruses are envisioned.
Systematic Parameterization of Lignin for the CHARMM Force Field

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

Vermaas, Joshua; Petridis, Loukas; Beckham, Gregg

Plant cell walls have three primary components, cellulose, hemicellulose, and lignin, the latter of which is a recalcitrant, aromatic heteropolymer that provides structure to plants, water and nutrient transport through plant tissues, and a highly effective defense against pathogens. Overcoming the recalcitrance of lignin is key to effective biomass deconstruction, which would in turn enable the use of biomass as a feedstock for industrial processes. Our understanding of lignin structure in the plant cell wall is hampered by the limitations of the available lignin forcefields, which currently only account for a single linkage between lignins and lack explicit parameterization formore » emerging lignin structures both from natural variants and engineered lignin structures. Since polymerization of lignin occurs via radical intermediates, multiple C-O and C-C linkages have been isolated , and the current force field only represents a small subset of lignin the diverse lignin structures found in plants. In order to take into account the wide range of lignin polymerization chemistries, monomers and dimer combinations of C-, H-, G-, and S-lignins as well as with hydroxycinnamic acid linkages were subjected to extensive quantum mechanical calculations to establish target data from which to build a complete molecular mechanics force field tuned specifically for diverse lignins. This was carried out in a GPU-accelerated global optimization process, whereby all molecules were parameterized simultaneously using the same internal parameter set. By parameterizing lignin specifically, we are able to more accurately represent the interactions and conformations of lignin monomers and dimers relative to a general force field. This new force field will enables computational researchers to study the effects of different linkages on the structure of lignin, as well as construct more accurate plant cell wall models based on observed statistical distributions of lignin that differ between disparate feedstocks, and guide further lignin engineering efforts.« less
Density-Functional Theory with Dispersion-Correcting Potentials for Methane: Bridging the Efficiency and Accuracy Gap between High-Level Wave Function and Classical Molecular Mechanics Methods.

PubMed

Torres, Edmanuel; DiLabio, Gino A

2013-08-13

Large clusters of noncovalently bonded molecules can only be efficiently modeled by classical mechanics simulations. One prominent challenge associated with this approach is obtaining force-field parameters that accurately describe noncovalent interactions. High-level correlated wave function methods, such as CCSD(T), are capable of correctly predicting noncovalent interactions, and are widely used to produce reference data. However, high-level correlated methods are generally too computationally costly to generate the critical reference data required for good force-field parameter development. In this work we present an approach to generate Lennard-Jones force-field parameters to accurately account for noncovalent interactions. We propose the use of a computational step that is intermediate to CCSD(T) and classical molecular mechanics, that can bridge the accuracy and computational efficiency gap between them, and demonstrate the efficacy of our approach with methane clusters. On the basis of CCSD(T)-level binding energy data for a small set of methane clusters, we develop methane-specific, atom-centered, dispersion-correcting potentials (DCPs) for use with the PBE0 density-functional and 6-31+G(d,p) basis sets. We then use the PBE0-DCP approach to compute a detailed map of the interaction forces associated with the removal of a single methane molecule from a cluster of eight methane molecules and use this map to optimize the Lennard-Jones parameters for methane. The quality of the binding energies obtained by the Lennard-Jones parameters we obtained is assessed on a set of methane clusters containing from 2 to 40 molecules. Our Lennard-Jones parameters, used in combination with the intramolecular parameters of the CHARMM force field, are found to closely reproduce the results of our dispersion-corrected density-functional calculations. The approach outlined can be used to develop Lennard-Jones parameters for any kind of molecular system.
Glycan Reader is improved to recognize most sugar types and chemical modifications in the Protein Data Bank.

PubMed

Park, Sang-Jun; Lee, Jumin; Patel, Dhilon S; Ma, Hongjing; Lee, Hui Sun; Jo, Sunhwan; Im, Wonpil

2017-10-01

Glycans play a central role in many essential biological processes. Glycan Reader was originally developed to simplify the reading of Protein Data Bank (PDB) files containing glycans through the automatic detection and annotation of sugars and glycosidic linkages between sugar units and to proteins, all based on atomic coordinates and connectivity information. Carbohydrates can have various chemical modifications at different positions, making their chemical space much diverse. Unfortunately, current PDB files do not provide exact annotations for most carbohydrate derivatives and more than 50% of PDB glycan chains have at least one carbohydrate derivative that could not be correctly recognized by the original Glycan Reader. Glycan Reader has been improved and now identifies most sugar types and chemical modifications (including various glycolipids) in the PDB, and both PDB and PDBx/mmCIF formats are supported. CHARMM-GUI Glycan Reader is updated to generate the simulation system and input of various glycoconjugates with most sugar types and chemical modifications. It also offers a new functionality to edit the glycan structures through addition/deletion/modification of glycosylation types, sugar types, chemical modifications, glycosidic linkages, and anomeric states. The simulation system and input files can be used for CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS, Desmond, OpenMM, and CHARMM/OpenMM. Glycan Fragment Database in GlycanStructure.Org is also updated to provide an intuitive glycan sequence search tool for complex glycan structures with various chemical modifications in the PDB. http://www.charmm-gui.org/input/glycan and http://www.glycanstructure.org. wonpil@lehigh.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Balancing Force Field Protein–Lipid Interactions To Capture Transmembrane Helix–Helix Association

PubMed Central

2018-01-01

Atomistic simulations have recently been shown to be sufficiently accurate to reversibly fold globular proteins and have provided insights into folding mechanisms. Gaining similar understanding from simulations of membrane protein folding and association would be of great medical interest. All-atom simulations of the folding and assembly of transmembrane protein domains are much more challenging, not least due to very slow diffusion within the lipid bilayer membrane. Here, we focus on a simple and well-characterized prototype of membrane protein folding and assembly, namely the dimerization of glycophorin A, a homodimer of single transmembrane helices. We have determined the free energy landscape for association of the dimer using the CHARMM36 force field. We find that the native structure is a metastable state, but not stable as expected from experimental estimates of the dissociation constant and numerous experimental structures obtained under a variety of conditions. We explore two straightforward approaches to address this problem and demonstrate that they result in stable dimers with dissociation constants consistent with experimental data. PMID:29424543
Experimental verification of force fields for molecular dynamics simulations using Gly-Pro-Gly-Gly.

PubMed

Aliev, Abil E; Courtier-Murias, Denis

2010-09-30

Experimental NMR verification of MD simulations using 12 different force fields (AMBER, CHARMM, GROMOS, and OPLS-AA) and 5 different water models has been undertaken to identify reliable MD protocols for structure and dynamics elucidations of small open chain peptides containing Gly and Pro. A conformationally flexible tetrapeptide Gly-Pro-Gly-Gly was selected for NMR (3)J-coupling, chemical shift, and internuclear distance measurements, followed by their calculations using 2 μs long MD simulations in water. In addition, Ramachandran population maps for Pro-2 and Gly-3 residues of GPGG obtained from MD simulations were used for detailed comparisons with similar maps from the protein data bank (PDB) for large number of Gly and Pro residues in proteins. The MD simulations revealed strong dependence of the populations and geometries of preferred backbone and side chain conformations, as well as the time scales of the peptide torsional transitions on the force field used. On the basis of the analysis of the measured and calculated data, AMBER99SB is identified as the most reliable force field for reproducing NMR measured parameters, which are dependent on the peptide backbone and the Pro side chain geometries and dynamics. Ramachandran maps showing the dependence of conformational populations as a function of backbone ϕ/ψ angles for Pro-2 and Gly-3 residues of GPGG from MD simulations using AMBER99SB, AMBER03, and CHARMM were found to resemble similar maps for Gly and Pro residues from the PDB survey. Three force fields (AMBER99, AMBER99ϕ, and AMBER94) showed the least satisfactory agreement with both the solution NMR and the PDB survey data. The poor performance of these force fields is attributed to their propensity to overstabilize helical peptide backbone conformations at the Pro-2 and Gly-3 residues. On the basis of the similarity of the MD and PDB Ramachandran plots, the following sequence of transitions is suggested for the Gly backbone conformation: α(L) ⇆ β(PR) ⇆ β(S) ⇆ β(P) ⇆ α, where backbone secondary structures α(L) and α are associated with helices and turns, β(P) and β(PR) correspond to the left- and right-handed polyproline II structures and β(S) denotes the fully stretched backbone conformation. Compared to the force field dependence, less significant, but noteworthy, variations in the populations of the peptide backbone conformations were observed. For different solvent models considered, a correlation was noted between the number of torsional transitions in GPGG and the water self-diffusion coefficient on using TIP3P, TIP4P, and TIP5P models. In addition to MD results, we also report DFT derived Karplus relationships for Gly and Pro residues using B972 and B3LYP functionals.
Are Current Atomistic Force Fields Accurate Enough to Study Proteins in Crowded Environments?

PubMed Central

Petrov, Drazen; Zagrovic, Bojan

2014-01-01

The high concentration of macromolecules in the crowded cellular interior influences different thermodynamic and kinetic properties of proteins, including their structural stabilities, intermolecular binding affinities and enzymatic rates. Moreover, various structural biology methods, such as NMR or different spectroscopies, typically involve samples with relatively high protein concentration. Due to large sampling requirements, however, the accuracy of classical molecular dynamics (MD) simulations in capturing protein behavior at high concentration still remains largely untested. Here, we use explicit-solvent MD simulations and a total of 6.4 µs of simulated time to study wild-type (folded) and oxidatively damaged (unfolded) forms of villin headpiece at 6 mM and 9.2 mM protein concentration. We first perform an exhaustive set of simulations with multiple protein molecules in the simulation box using GROMOS 45a3 and 54a7 force fields together with different types of electrostatics treatment and solution ionic strengths. Surprisingly, the two villin headpiece variants exhibit similar aggregation behavior, despite the fact that their estimated aggregation propensities markedly differ. Importantly, regardless of the simulation protocol applied, wild-type villin headpiece consistently aggregates even under conditions at which it is experimentally known to be soluble. We demonstrate that aggregation is accompanied by a large decrease in the total potential energy, with not only hydrophobic, but also polar residues and backbone contributing substantially. The same effect is directly observed for two other major atomistic force fields (AMBER99SB-ILDN and CHARMM22-CMAP) as well as indirectly shown for additional two (AMBER94, OPLS-AAL), and is possibly due to a general overestimation of the potential energy of protein-protein interactions at the expense of water-water and water-protein interactions. Overall, our results suggest that current MD force fields may distort the picture of protein behavior in biologically relevant crowded environments. PMID:24854339
Balancing the Interactions of Ions, Water, and DNA in the Drude Polarizable Force Field

PubMed Central

2015-01-01

Recently we presented a first-generation all-atom Drude polarizable force field for DNA based on the classical Drude oscillator model, focusing on optimization of key dihedral angles followed by extensive validation of the force field parameters. Presently, we describe the procedure for balancing the electrostatic interactions between ions, water, and DNA as required for development of the Drude force field for DNA. The proper balance of these interactions is shown to impact DNA stability and subtler conformational properties, including the conformational equilibrium between the BI and BII states, and the A and B forms of DNA. The parametrization efforts were simultaneously guided by gas-phase quantum mechanics (QM) data on small model compounds and condensed-phase experimental data on the hydration and osmotic properties of biologically relevant ions and their solutions, as well as theoretical predictions for ionic distribution around DNA oligomer. In addition, fine-tuning of the internal base parameters was performed to obtain the final DNA model. Notably, the Drude model is shown to more accurately reproduce counterion condensation theory predictions of DNA charge neutralization by the condensed ions as compared to the CHARMM36 additive DNA force field, indicating an improved physical description of the forces dictating the ionic solvation of DNA due to the explicit treatment of electronic polarizability. In combination with the polarizable DNA force field, the availability of Drude polarizable parameters for proteins, lipids, and carbohydrates will allow for simulation studies of heterogeneous biological systems. PMID:24874104
Interpolation schemes for peptide rearrangements.

PubMed

Bauer, Marianne S; Strodel, Birgit; Fejer, Szilard N; Koslover, Elena F; Wales, David J

2010-02-07

A variety of methods (in total seven) comprising different combinations of internal and Cartesian coordinates are tested for interpolation and alignment in connection attempts for polypeptide rearrangements. We consider Cartesian coordinates, the internal coordinates used in CHARMM, and natural internal coordinates, each of which has been interfaced to the OPTIM code and compared with the corresponding results for united-atom force fields. We show that aligning the methylene hydrogens to preserve the sign of a local dihedral angle, rather than minimizing a distance metric, provides significant improvements with respect to connection times and failures. We also demonstrate the superiority of natural coordinate methods in conjunction with internal alignment. Checking the potential energy of the interpolated structures can act as a criterion for the choice of the interpolation coordinate system, which reduces failures and connection times significantly.
Force-field parametrization and molecular dynamics simulations of Congo red

NASA Astrophysics Data System (ADS)

Król, Marcin; Borowski, Tomasz; Roterman, Irena; Piekarska, Barbara; Stopa, Barbara; Rybarska, Joanna; Konieczny, Leszek

2004-01-01

Congo red, a diazo dye widely used in medical diagnosis, is known to form supramolecular systems in solution. Such a supramolecular system may interact with various proteins. In order to examine the nature of such complexes empirical force field parameters for the Congo red molecule were developed. The parametrization of bonding terms closely followed the methodology used in the development of the charmm22 force field, except for the calculation of charges. Point charges were calculated from a fit to a quantum mechanically derived electrostatic potential using the CHELP-BOW method. Obtained parameters were tested in a series of molecular dynamics simulations of both a single molecule and a micelle composed of Congo red molecules. It is shown that newly developed parameters define a stable minimum on the hypersurface of the potential energy and crystal and ab initio geometries and rotational barriers are well reproduced. Furthermore, rotations around C-N bonds are similar to torsional vibrations observed in crystals of diphenyl-diazene, which confirms that the flexibility of the molecule is correct. Comparison of results obtained from micelles molecular dynamics simulations with experimental data shows that the thermal dependence of micelle creation is well reproduced.
Flexible CDOCKER: Development and application of a pseudo-explicit structure-based docking method within CHARMM

PubMed Central

Gagnon, Jessica K.; Law, Sean M.; Brooks, Charles L.

2016-01-01

Protein-ligand docking is a commonly used method for lead identification and refinement. While traditional structure-based docking methods represent the receptor as a rigid body, recent developments have been moving toward the inclusion of protein flexibility. Proteins exist in an inter-converting ensemble of conformational states, but effectively and efficiently searching the conformational space available to both the receptor and ligand remains a well-appreciated computational challenge. To this end, we have developed the Flexible CDOCKER method as an extension of the family of complete docking solutions available within CHARMM. This method integrates atomically detailed side chain flexibility with grid-based docking methods, maintaining efficiency while allowing the protein and ligand configurations to explore their conformational space simultaneously. This is in contrast to existing approaches that use induced-fit like sampling, such as Glide or Autodock, where the protein or the ligand space is sampled independently in an iterative fashion. Presented here are developments to the CHARMM docking methodology to incorporate receptor flexibility and improvements to the sampling protocol as demonstrated with re-docking trials on a subset of the CCDC/Astex set. These developments within CDOCKER achieve docking accuracy competitive with or exceeding the performance of other widely utilized docking programs. PMID:26691274
Flexible CDOCKER: Development and application of a pseudo-explicit structure-based docking method within CHARMM.

PubMed

Gagnon, Jessica K; Law, Sean M; Brooks, Charles L

2016-03-30

Protein-ligand docking is a commonly used method for lead identification and refinement. While traditional structure-based docking methods represent the receptor as a rigid body, recent developments have been moving toward the inclusion of protein flexibility. Proteins exist in an interconverting ensemble of conformational states, but effectively and efficiently searching the conformational space available to both the receptor and ligand remains a well-appreciated computational challenge. To this end, we have developed the Flexible CDOCKER method as an extension of the family of complete docking solutions available within CHARMM. This method integrates atomically detailed side chain flexibility with grid-based docking methods, maintaining efficiency while allowing the protein and ligand configurations to explore their conformational space simultaneously. This is in contrast to existing approaches that use induced-fit like sampling, such as Glide or Autodock, where the protein or the ligand space is sampled independently in an iterative fashion. Presented here are developments to the CHARMM docking methodology to incorporate receptor flexibility and improvements to the sampling protocol as demonstrated with re-docking trials on a subset of the CCDC/Astex set. These developments within CDOCKER achieve docking accuracy competitive with or exceeding the performance of other widely utilized docking programs. © 2015 Wiley Periodicals, Inc.
All-Atom Four-Body Knowledge-Based Statistical Potentials to Distinguish Native Protein Structures from Nonnative Folds

PubMed Central

2017-01-01

Recent advances in understanding protein folding have benefitted from coarse-grained representations of protein structures. Empirical energy functions derived from these techniques occasionally succeed in distinguishing native structures from their corresponding ensembles of nonnative folds or decoys which display varying degrees of structural dissimilarity to the native proteins. Here we utilized atomic coordinates of single protein chains, comprising a large diverse training set, to develop and evaluate twelve all-atom four-body statistical potentials obtained by exploring alternative values for a pair of inherent parameters. Delaunay tessellation was performed on the atomic coordinates of each protein to objectively identify all quadruplets of interacting atoms, and atomic potentials were generated via statistical analysis of the data and implementation of the inverted Boltzmann principle. Our potentials were evaluated using benchmarking datasets from Decoys-‘R'-Us, and comparisons were made with twelve other physics- and knowledge-based potentials. Ranking 3rd, our best potential tied CHARMM19 and surpassed AMBER force field potentials. We illustrate how a generalized version of our potential can be used to empirically calculate binding energies for target-ligand complexes, using HIV-1 protease-inhibitor complexes for a practical application. The combined results suggest an accurate and efficient atomic four-body statistical potential for protein structure prediction and assessment. PMID:29119109
Coherent microscopic picture for urea-induced denaturation of proteins.

PubMed

Yang, Zaixing; Xiu, Peng; Shi, Biyun; Hua, Lan; Zhou, Ruhong

2012-08-02

In a previous study, we explored the mechanism of urea-induced denaturation of proteins by performing molecular dynamics (MD) simulations of hen lysozyme in 8 M urea and supported the "direct interaction mechanism" whereby urea denatures protein via dispersion interaction (Hua, L.; Zhou, R. H.; Thirumalai, D.; Berne, B. J. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 16928). Here we perform large scale MD simulations of five representative protein/peptide systems in aqueous urea to investigate if the above mechanism is common to other proteins. In all cases, accumulations of urea around proteins/peptide are observed, suggesting that urea denatures proteins by directly attacking protein backbones and side chains rather than indirectly disrupting water structure as a "water breaker". Consistent with our previous case study of lysozyme, the current energetic analyses with five protein/peptide systems reveal that urea's preferential binding to proteins mainly comes from urea's stronger dispersion interactions with proteins than with bulk solution, whereas the electrostatic (hydrogen-bonded) interactions only play a relatively minor (even negative) role during this denaturation process. Furthermore, the simulations of the peptide system at different urea concentrations (8 and 4.5 M), and with different force fields (CHARMM and OPLSAA) suggest that the above mechanism is robust, independent of the urea concentration and force field used. Last, we emphasize the importance of periodic boundary conditions in pairwise energetic analyses. This article provides a comprehensive study on the physical mechanism of urea-induced protein denaturation and suggests that the "dispersion-interaction-driven" mechanism should be general.
Chloride Ion Transport by the E. coli CLC Cl-/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study.

PubMed

Wang, Chun-Hung; Duster, Adam W; Aydintug, Baris O; Zarecki, MacKenzie G; Lin, Hai

2018-01-01

We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl - ion migration through the transmembrane domain of a prototypical E. coli CLC Cl - /H + antiporter by employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found to be critical for full access of the channel entrance by Cl - . Moving the anion into the external binding site (S ext ) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl - traveled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl - exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl - along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing π bonds (e.g., the Tyr445 side chain), while the charges of the H atoms coordinating Cl - changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers (~10 kcal/mol) than the MM PMF (~2 kcal/mol). Binding energy calculations indicated that the interactions between Cl - and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing π bonds, missing the stabilizations of the Cl - ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl - transport.
Chloride Ion Transport by the E. coli CLC Cl−/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study

PubMed Central

Wang, Chun-Hung; Duster, Adam W.; Aydintug, Baris O.; Zarecki, MacKenzie G.; Lin, Hai

2018-01-01

We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl− ion migration through the transmembrane domain of a prototypical E. coli CLC Cl−/H+ antiporter by employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found to be critical for full access of the channel entrance by Cl−. Moving the anion into the external binding site (Sext) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl− traveled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl− exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl− along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing π bonds (e.g., the Tyr445 side chain), while the charges of the H atoms coordinating Cl− changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers (~10 kcal/mol) than the MM PMF (~2 kcal/mol). Binding energy calculations indicated that the interactions between Cl− and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing π bonds, missing the stabilizations of the Cl− ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl− transport. PMID:29594103
Chloride Ion Transport by the E. coli CLC Cl–/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study

NASA Astrophysics Data System (ADS)

Wang, Chun-Hung; Duster, Adam W.; Aydintug, Baris O.; Zarecki, MacKenzie G.; Lin, Hai

2018-03-01

We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl– ion migration through the transmembrane domain of a prototypical E. coli CLC Cl–/H+ antiporter employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found critical to full access of the channel entrance by Cl–. Moving the anion into the external binding site (Sext) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl– travelled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl– exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl– along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing pi bonds (e.g. the Tyr445 side chain), while the charges of the H atoms coordinating Cl– changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers ( 10 kcal/mol) than the MM PMF ( 2 kcal/mol). Binding energy calculations indicated that the interactions between Cl– and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing pi bonds, missing the stabilizations of the Cl– ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl– transport.
Critical Comparison of Biomembrane Force Fields: Protein-Lipid Interactions at the Membrane Interface.

PubMed

Sandoval-Perez, Angelica; Pluhackova, Kristyna; Böckmann, Rainer A

2017-05-09

Molecular dynamics (MD) simulations offer the possibility to study biological processes at high spatial and temporal resolution often not reachable by experiments. Corresponding biomolecular force field parameters have been developed for a wide variety of molecules ranging from inorganic ligands and small organic molecules over proteins and lipids to nucleic acids. Force fields have typically been parametrized and validated on thermodynamic observables and structural characteristics of individual compounds, e.g. of soluble proteins or lipid bilayers. Less strictly, due to the added complexity and missing experimental data to compare to, force fields have hardly been tested on the properties of mixed systems, e.g. on protein-lipid systems. Their selection and combination for mixed systems is further complicated by the partially differing parametrization strategies. Additionally, the presence of other compounds in the system may shift the subtle balance of force field parameters. Here, we assessed the protein-lipid interactions as described in the four atomistic force fields GROMOS54a7, CHARMM36 and the two force field combinations Amber14sb/Slipids and Amber14sb/Lipid14. Four observables were compared, focusing on the membrane-water interface: the conservation of the secondary structure of transmembrane proteins, the positioning of transmembrane peptides relative to the lipid bilayer, the insertion depth of side chains of unfolded peptides absorbed at the membrane interface, and the ability to reproduce experimental insertion energies of Wimley-White peptides at the membrane interface. Significant differences between the force fields were observed that affect e.g. membrane insertion depths and tilting of transmembrane peptides.
Development of a conformational search strategy for flexible ligands: A study of the potent μ-selective opioid analgesic fentanyl

NASA Astrophysics Data System (ADS)

Cometta-Morini, Chiara; Loew, Gilda H.

1991-08-01

An extensive conformational search of the potent opioid analgesic, fentanyl, was performed using the semiempirical quantum mechanical method AM1 and the CHARMm potential energy function. A combination of two procedures was used to search the conformational space for fentanyl, which included nested dihedral scans, geometry optimization and molecular dynamics simulation at different temperatures. In addition, the effect of a continuum solvent environment was taken into account by use of appropriate values for the dielectric constant in the CHARMm computations. The results of the conformational search allowed the determination of the probable conformation of fentanyl in polar and nonpolar solvents and of three candidate conformers for its bioactive form.

Comparative Study of the Energetics of Ion Permeation in Kv1.2 and KcsA Potassium Channels

PubMed Central

Baştuğ, Turgut; Kuyucak, Serdar

2011-01-01

Biological ion channels rely on a multi-ion transport mechanism for fast yet selective permeation of ions. The crystal structure of the KcsA potassium channel provided the first microscopic picture of this process. A similar mechanism is assumed to operate in all potassium channels, but the validity of this assumption has not been well investigated. Here, we examine the energetics of ion permeation in Shaker Kv1.2 and KcsA channels, which exemplify the six-transmembrane voltage-gated and two-transmembrane inward-rectifier channels. We study the feasibility of binding a third ion to the filter and the concerted motion of ions in the channel by constructing the potential of mean force for K+ ions in various configurations. For both channels, we find that a pair of K+ ions can move almost freely within the filter, but a relatively large free-energy barrier hinders the K+ ion from stepping outside the filter. We discuss the effect of the CMAP dihedral energy correction that was recently incorporated into the CHARMM force field on ion permeation dynamics. PMID:21281577
E-novo: an automated workflow for efficient structure-based lead optimization.

PubMed

Pearce, Bradley C; Langley, David R; Kang, Jia; Huang, Hongwei; Kulkarni, Amit

2009-07-01

An automated E-Novo protocol designed as a structure-based lead optimization tool was prepared through Pipeline Pilot with existing CHARMm components in Discovery Studio. A scaffold core having 3D binding coordinates of interest is generated from a ligand-bound protein structural model. Ligands of interest are generated from the scaffold using an R-group fragmentation/enumeration tool within E-Novo, with their cores aligned. The ligand side chains are conformationally sampled and are subjected to core-constrained protein docking, using a modified CHARMm-based CDOCKER method to generate top poses along with CDOCKER energies. In the final stage of E-Novo, a physics-based binding energy scoring function ranks the top ligand CDOCKER poses using a more accurate Molecular Mechanics-Generalized Born with Surface Area method. Correlation of the calculated ligand binding energies with experimental binding affinities were used to validate protocol performance. Inhibitors of Src tyrosine kinase, CDK2 kinase, beta-secretase, factor Xa, HIV protease, and thrombin were used to test the protocol using published ligand crystal structure data within reasonably defined binding sites. In-house Respiratory Syncytial Virus inhibitor data were used as a more challenging test set using a hand-built binding model. Least squares fits for all data sets suggested reasonable validation of the protocol within the context of observed ligand binding poses. The E-Novo protocol provides a convenient all-in-one structure-based design process for rapid assessment and scoring of lead optimization libraries.
CHARMM Force-Fields with Modified Polyphosphate Parameters Allow Stable Simulation of the ATP-Bound Structure of Ca(2+)-ATPase.

PubMed

Komuro, Yasuaki; Re, Suyong; Kobayashi, Chigusa; Muneyuki, Eiro; Sugita, Yuji

2014-09-09

Adenosine triphosphate (ATP) is an indispensable energy source in cells. In a wide variety of biological phenomena like glycolysis, muscle contraction/relaxation, and active ion transport, chemical energy released from ATP hydrolysis is converted to mechanical forces to bring about large-scale conformational changes in proteins. Investigation of structure-function relationships in these proteins by molecular dynamics (MD) simulations requires modeling of ATP in solution and ATP bound to proteins with accurate force-field parameters. In this study, we derived new force-field parameters for the triphosphate moiety of ATP based on the high-precision quantum calculations of methyl triphosphate. We tested our new parameters on membrane-embedded sarcoplasmic reticulum Ca(2+)-ATPase and four soluble proteins. The ATP-bound structure of Ca(2+)-ATPase remains stable during MD simulations, contrary to the outcome in shorter simulations using original parameters. Similar results were obtained with the four ATP-bound soluble proteins. The new force-field parameters were also tested by investigating the range of conformations sampled during replica-exchange MD simulations of ATP in explicit water. Modified parameters allowed a much wider range of conformational sampling compared with the bias toward extended forms with original parameters. A diverse range of structures agrees with the broad distribution of ATP conformations in proteins deposited in the Protein Data Bank. These simulations suggest that the modified parameters will be useful in studies of ATP in solution and of the many ATP-utilizing proteins.
Simulations Meet Experiment to Reveal New Insights into DNA Intrinsic Mechanics

PubMed Central

Ben Imeddourene, Akli; Elbahnsi, Ahmad; Guéroult, Marc; Oguey, Christophe; Foloppe, Nicolas; Hartmann, Brigitte

2015-01-01

The accurate prediction of the structure and dynamics of DNA remains a major challenge in computational biology due to the dearth of precise experimental information on DNA free in solution and limitations in the DNA force-fields underpinning the simulations. A new generation of force-fields has been developed to better represent the sequence-dependent B-DNA intrinsic mechanics, in particular with respect to the BI ↔ BII backbone equilibrium, which is essential to understand the B-DNA properties. Here, the performance of MD simulations with the newly updated force-fields Parmbsc0εζOLI and CHARMM36 was tested against a large ensemble of recent NMR data collected on four DNA dodecamers involved in nucleosome positioning. We find impressive progress towards a coherent, realistic representation of B-DNA in solution, despite residual shortcomings. This improved representation allows new and deeper interpretation of the experimental observables, including regarding the behavior of facing phosphate groups in complementary dinucleotides, and their modulation by the sequence. It also provides the opportunity to extensively revisit and refine the coupling between backbone states and inter base pair parameters, which emerges as a common theme across all the complementary dinucleotides. In sum, the global agreement between simulations and experiment reveals new aspects of intrinsic DNA mechanics, a key component of DNA-protein recognition. PMID:26657165
New Force Field Model for Propylene Glycol: Insight to Local Structure and Dynamics.

PubMed

Ferreira, Elisabete S C; Voroshylova, Iuliia V; Koverga, Volodymyr A; Pereira, Carlos M; Cordeiro, M Natália D S

2017-12-07

In this work we developed a new force field model (FFM) for propylene glycol (PG) based on the OPLS all-atom potential. The OPLS potential was refined using quantum chemical calculations, taking into account the densities and self-diffusion coefficients. The validation of this new FFM was carried out based on a wide range of physicochemical properties, such as density, enthalpy of vaporization, self-diffusion coefficients, isothermal compressibility, surface tension, and shear viscosity. The molecular dynamics (MD) simulations were performed over a large range of temperatures (293.15-373.15 K). The comparison with other force field models, such as OPLS, CHARMM27, and GAFF, revealed a large improvement of the results, allowing a better agreement with experimental data. Specific structural properties (radial distribution functions, hydrogen bonding and spatial distribution functions) were then analyzed in order to support the adequacy of the proposed FFM. Pure propylene glycol forms a continuous phase, displaying no microstructures. It is shown that the developed FFM gives rise to suitable results not only for pure propylene glycol but also for mixtures by testing its behavior for a 50 mol % aqueous propylene glycol solution. Furthermore, it is demonstrated that the addition of water to the PG phase produces a homogeneous solution and that the hydration interactions prevail over the propylene glycol self-association interactions.
Convergence and reproducibility in molecular dynamics simulations of the DNA duplex d(GCACGAACGAACGAACGC)

PubMed Central

Galindo-Murillo, Rodrigo; Roe, Daniel R.; Cheatham, Thomas E.

2014-01-01

Background The structure and dynamics of DNA are critically related to its function. Molecular dynamics (MD) simulations augment experiment by providing detailed information about the atomic motions. However, to date the simulations have not been long enough for convergence of the dynamics and structural properties of DNA. Methods MD simulations performed with AMBER using the ff99SB force field with the parmbsc0 modifications, including ensembles of independent simulations, were compared to long timescale MD performed with the specialized Anton MD engine on the B-DNA structure d(GCACGAACGAACGAACGC). To assess convergence, the decay of the average RMSD values over longer and longer time intervals was evaluated in addition to assessing convergence of the dynamics via the Kullback-Leibler divergence of principal component projection histograms. Results These MD simulations —including one of the longest simulations of DNA published to date at ~44 μs—surprisingly suggest that the structure and dynamics of the DNA helix, neglecting the terminal base pairs, are essentially fully converged on the ~1–5 μs timescale. Conclusions We can now reproducibly converge the structure and dynamics of B-DNA helices, omitting the terminal base pairs, on the μs time scale with both the AMBER and CHARMM C36 nucleic acid force fields. Results from independent ensembles of simulations starting from different initial conditions, when aggregated, match the results from long timescale simulations on the specialized Anton MD engine. General Significance With access to large-scale GPU resources or the specialized MD engine “Anton” it is possibly for a variety of molecular systems to reproducibly and reliably converge the conformational ensemble of sampled structures. PMID:25219455
LAMMPS strong scaling performance optimization on Blue Gene/Q

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

Coffman, Paul; Jiang, Wei; Romero, Nichols A.

2014-11-12

LAMMPS "Large-scale Atomic/Molecular Massively Parallel Simulator" is an open-source molecular dynamics package from Sandia National Laboratories. Significant performance improvements in strong-scaling and time-to-solution for this application on IBM's Blue Gene/Q have been achieved through computational optimizations of the OpenMP versions of the short-range Lennard-Jones term of the CHARMM force field and the long-range Coulombic interaction implemented with the PPPM (particle-particle-particle mesh) algorithm, enhanced by runtime parameter settings controlling thread utilization. Additionally, MPI communication performance improvements were made to the PPPM calculation by re-engineering the parallel 3D FFT to use MPICH collectives instead of point-to-point. Performance testing was done using anmore » 8.4-million atom simulation scaling up to 16 racks on the Mira system at Argonne Leadership Computing Facility (ALCF). Speedups resulting from this effort were in some cases over 2x.« less
Self-Assembly of Alkylammonium Chains on Montmorillonite: Effect of Interlayer Cations, CEC, and Chain Length

NASA Astrophysics Data System (ADS)

Chen, Hua; Li, Yingjun; Zhou, Yuanlin; Wang, Shanqiang; Zheng, Jian; He, Jiacai

2017-12-01

Recently, polymeric materials have been filled with synthetic or natural inorganic compounds in order to improve their properties. Especially, polymer clay nanocomposites have attracted both academic and industrial attention. Currently, the structure and physical phenomena of organoclays at molecular level are difficultly explained by existing experimental techniques. In this work, molecular dynamics (MD) simulation was executed using the CLAYFF and CHARMM force fields to evaluate the structural properties of organoclay such as basal spacing, interlayer density, energy and the arrangement of alkyl chains in the interlayer spacing. Our results are in good agreement with available experimental or other simulation data. The effects of interlayer cations (Na+, K+, Ca2+), the cation exchange capacity, and the alkyl chain length on the basal spacing and the structural properties are estimated. These simulations are expected to presage the microstructure of organo-montmorillonite and lead relevant engineering applications.
Computational study of some benzamidine-based inhibitors of thrombin-like snake venom proteinases

NASA Astrophysics Data System (ADS)

Henriques, Elsa S.; Nascimento, Marco A. C.; Ramos, Maria João

Pit viper venoms contain a number of serine proteinases that, despite their observed coagulant thrombin-like action in vitro, exhibit a paradoxical benign defibrinogenating (anticoagulant) action in vivo, with clinical applications in preventing thrombi and improved blood circulation. Considering that several benzamidine-based inhibitors, some highly selective to thrombin, also inhibit the enzymatic activity of such venombins, the modeling of their enzyme-inhibitor interactions could provide valuable information on the topological factors that determine the divergences in activity. The first step, and the object of the present study, was to derive the necessary set of parameters, consistent with the CHARMM force field, and to perform molecular dynamics (MD) simulations on a few selected representatives of the inhibitors in question under physiological conditions. Bonding and van der Waals parameters were derived by analogy to similar ones in the existing force field. Net atomic charges were obtained with a restrained fitting to the molecular electrostatic potential generated at B3LYP/6-31G(d) level. The parameters were refined to reproduce the available experimental geometries and crystal data, and the MD simulations of the free inhibitors in aqueous solution at 298 K provided an insightful description of their available conformational space.
Structural variations of single and tandem mismatches in RNA duplexes: a joint MD simulation and crystal structure database analysis.

PubMed

Halder, Sukanya; Bhattacharyya, Dhananjay

2012-10-04

Internal loops within RNA duplex regions are formed by single or tandem basepairing mismatches with flanking canonical Watson-Crick basepairs on both sides. They are the most common motif observed in RNA secondary structures and play integral functional and structural roles. In this report, we have studied the structural features of 1 × 1, 2 × 2, and 3 × 3 internal loops using all-atom molecular dynamics (MD) simulation technique with explicit solvent model. As MD simulation is intricately dependent on the choice of force-field and these are often rather approximate, we have used both the most popular force-fields for nucleic acids-CHARMM27 and AMBER94-for a comparative analysis. We find that tandem noncanonical basepairs forming 2 × 2 and 3 × 3 internal loops are considerably more stable than the single mismatches forming 1 × 1 internal loops, irrespective of the force field. We have also analyzed crystal structure database to study the conservation of these helical fragments in the corresponding sets of RNA structures. We observe that the nature of stability in MD simulations mimic their fluctuating natures in crystal data sets also, probably indicating reliable natures of both the force fields to reproduce experimental results. We also notice significant structural changes in the wobble G:U basepairs present in these double helical stretches, leading to a biphasic stability for these wobble pairs to release the deformational strains introduced by internal loops within duplex regions.
Thermodynamically consistent force fields for the assembly of inorganic, organic, and biological nanostructures: the INTERFACE force field.

PubMed

Heinz, Hendrik; Lin, Tzu-Jen; Mishra, Ratan Kishore; Emami, Fateme S

2013-02-12

The complexity of the molecular recognition and assembly of biotic-abiotic interfaces on a scale of 1 to 1000 nm can be understood more effectively using simulation tools along with laboratory instrumentation. We discuss the current capabilities and limitations of atomistic force fields and explain a strategy to obtain dependable parameters for inorganic compounds that has been developed and tested over the past decade. Parameter developments include several silicates, aluminates, metals, oxides, sulfates, and apatites that are summarized in what we call the INTERFACE force field. The INTERFACE force field operates as an extension of common harmonic force fields (PCFF, COMPASS, CHARMM, AMBER, GROMACS, and OPLS-AA) by employing the same functional form and combination rules to enable simulations of inorganic-organic and inorganic-biomolecular interfaces. The parametrization builds on an in-depth understanding of physical-chemical properties on the atomic scale to assign each parameter, especially atomic charges and van der Waals constants, as well as on the validation of macroscale physical-chemical properties for each compound in comparison to measurements. The approach eliminates large discrepancies between computed and measured bulk and surface properties of up to 2 orders of magnitude using other parametrization protocols and increases the transferability of the parameters by introducing thermodynamic consistency. As a result, a wide range of properties can be computed in quantitative agreement with experiment, including densities, surface energies, solid-water interface tensions, anisotropies of interfacial energies of different crystal facets, adsorption energies of biomolecules, and thermal and mechanical properties. Applications include insight into the assembly of inorganic-organic multiphase materials, the recognition of inorganic facets by biomolecules, growth and shape preferences of nanocrystals and nanoparticles, as well as thermal transitions and nanomechanics. Limitations and opportunities for further development are also described.
An improved DNA force field for ssDNA interactions with gold nanoparticles

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

Jiang, Xiankai; Huai, Ping; Fan, Chunhai

The widespread applications of single-stranded DNA (ssDNA) conjugated gold nanoparticles (AuNPs) have spurred an increasing interest in the interactions between ssDNA and AuNPs. Despite extensive studies using the most sophisticated experimental techniques, the detailed molecular mechanisms still remain largely unknown. Large scale molecular dynamics (MD) simulations can thus be used to supplement experiments by providing complementary information about ssDNA-AuNP interactions. However, up to now, all modern force fields for DNA were developed based on the properties of double-stranded DNA (dsDNA) molecules, which have hydrophilic outer backbones “protecting” hydrophobic inner nucleobases from water. Without the double-helix structure of dsDNA and thusmore » the “protection” by the outer backbone, the nucleobases of ssDNA are directly exposed to solvent, and their behavior in water is very different from that of dsDNA, especially at the interface with nanoparticles. In this work, we have improved the force field of ssDNA for use with nanoparticles, such as AuNPs, based on recent experimental results and quantum mechanics calculations. With the new improved force field, we demonstrated that a poly(A) sequence adsorbed on a AuNP surface is much more stable than a poly(T) sequence, which is consistent with recent experimental observations. On the contrary, the current standard force fields, including AMBER03, CHARMM27, and OPLSAA, all gave erroneous results as compared to experiments. The current improved force field is expected to have wide applications in the study of ssDNA with nanomaterials including AuNPs, which might help promote the development of ssDNA-based biosensors and other bionano-devices.« less
An improved DNA force field for ssDNA interactions with gold nanoparticles

NASA Astrophysics Data System (ADS)

Jiang, Xiankai; Gao, Jun; Huynh, Tien; Huai, Ping; Fan, Chunhai; Zhou, Ruhong; Song, Bo

2014-06-01

The widespread applications of single-stranded DNA (ssDNA) conjugated gold nanoparticles (AuNPs) have spurred an increasing interest in the interactions between ssDNA and AuNPs. Despite extensive studies using the most sophisticated experimental techniques, the detailed molecular mechanisms still remain largely unknown. Large scale molecular dynamics (MD) simulations can thus be used to supplement experiments by providing complementary information about ssDNA-AuNP interactions. However, up to now, all modern force fields for DNA were developed based on the properties of double-stranded DNA (dsDNA) molecules, which have hydrophilic outer backbones "protecting" hydrophobic inner nucleobases from water. Without the double-helix structure of dsDNA and thus the "protection" by the outer backbone, the nucleobases of ssDNA are directly exposed to solvent, and their behavior in water is very different from that of dsDNA, especially at the interface with nanoparticles. In this work, we have improved the force field of ssDNA for use with nanoparticles, such as AuNPs, based on recent experimental results and quantum mechanics calculations. With the new improved force field, we demonstrated that a poly(A) sequence adsorbed on a AuNP surface is much more stable than a poly(T) sequence, which is consistent with recent experimental observations. On the contrary, the current standard force fields, including AMBER03, CHARMM27, and OPLSAA, all gave erroneous results as compared to experiments. The current improved force field is expected to have wide applications in the study of ssDNA with nanomaterials including AuNPs, which might help promote the development of ssDNA-based biosensors and other bionano-devices.
An improved DNA force field for ssDNA interactions with gold nanoparticles.

PubMed

Jiang, Xiankai; Gao, Jun; Huynh, Tien; Huai, Ping; Fan, Chunhai; Zhou, Ruhong; Song, Bo

2014-06-21

The widespread applications of single-stranded DNA (ssDNA) conjugated gold nanoparticles (AuNPs) have spurred an increasing interest in the interactions between ssDNA and AuNPs. Despite extensive studies using the most sophisticated experimental techniques, the detailed molecular mechanisms still remain largely unknown. Large scale molecular dynamics (MD) simulations can thus be used to supplement experiments by providing complementary information about ssDNA-AuNP interactions. However, up to now, all modern force fields for DNA were developed based on the properties of double-stranded DNA (dsDNA) molecules, which have hydrophilic outer backbones "protecting" hydrophobic inner nucleobases from water. Without the double-helix structure of dsDNA and thus the "protection" by the outer backbone, the nucleobases of ssDNA are directly exposed to solvent, and their behavior in water is very different from that of dsDNA, especially at the interface with nanoparticles. In this work, we have improved the force field of ssDNA for use with nanoparticles, such as AuNPs, based on recent experimental results and quantum mechanics calculations. With the new improved force field, we demonstrated that a poly(A) sequence adsorbed on a AuNP surface is much more stable than a poly(T) sequence, which is consistent with recent experimental observations. On the contrary, the current standard force fields, including AMBER03, CHARMM27, and OPLSAA, all gave erroneous results as compared to experiments. The current improved force field is expected to have wide applications in the study of ssDNA with nanomaterials including AuNPs, which might help promote the development of ssDNA-based biosensors and other bionano-devices.
Solvation Thermodynamics of Oligoglycine with Respect to Chain Length and Flexibility.

PubMed

Drake, Justin A; Harris, Robert C; Pettitt, B Montgomery

2016-08-23

Oligoglycine is a backbone mimic for all proteins and is prevalent in the sequences of intrinsically disordered proteins. We have computed the absolute chemical potential of glycine oligomers at infinite dilution by simulation with the CHARMM36 and Amber ff12SB force fields. We performed a thermodynamic decomposition of the solvation free energy (ΔG(sol)) of Gly2-5 into enthalpic (ΔH(sol)) and entropic (ΔS(sol)) components as well as their van der Waals and electrostatic contributions. Gly2-5 was either constrained to a rigid/extended conformation or allowed to be completely flexible during simulations to assess the effects of flexibility on these thermodynamic quantities. For both rigid and flexible oligoglycine models, the decrease in ΔG(sol) with chain length is enthalpically driven with only weak entropic compensation. However, the apparent rates of decrease of ΔG(sol), ΔH(sol), ΔS(sol), and their elec and vdw components differ for the rigid and flexible models. Thus, we find solvation entropy does not drive aggregation for this system and may not explain the collapse of long oligoglycines. Additionally, both force fields yield very similar thermodynamic scaling relationships with respect to chain length despite both force fields generating different conformational ensembles of various oligoglycine chains. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Transferability of different classical force fields for right and left handed α-helices constructed from enantiomeric amino acids.

PubMed

Biswas, Santu; Sarkar, Sujit; Pandey, Prithvi Raj; Roy, Sudip

2016-02-21

Amino acids can form d and l enantiomers, of which the l enantiomer is abundant in nature. The naturally occurring l enantiomer has a greater preference for a right handed helical conformation, and the d enantiomer for a left handed helical conformation. The other conformations, that is, left handed helical conformations of the l enantiomers and right handed helical conformations of the d enantiomers, are not common. The energetic differences between left and right handed alpha helical peptide chains constructed from enantiomeric amino acids are investigated using quantum chemical calculations (using the M06/6-311g(d,p) level of theory). Further, the performances of commonly used biomolecular force fields (OPLS/AA, CHARMM27/CMAP and AMBER) to represent the different helical conformations (left and right handed) constructed from enantiomeric (D and L) amino acids are evaluated. 5- and 10-mer chains from d and l enantiomers of alanine, leucine, lysine, and glutamic acid, in right and left handed helical conformations, are considered in the study. Thus, in total, 32 α-helical polypeptides (4 amino acids × 4 conformations of 5-mer and 10-mer) are studied. Conclusions, with regards to the performance of the force fields, are derived keeping the quantum optimized geometry as the benchmark, and on the basis of phi and psi angle calculations, hydrogen bond analysis, and different long range helical order parameters.
Further theoretical insight into the reaction mechanism of the hepatitis C NS3/NS4A serine protease

NASA Astrophysics Data System (ADS)

Martínez-González, José Ángel; Rodríguez, Alex; Puyuelo, María Pilar; González, Miguel; Martínez, Rodrigo

2015-01-01

The main reactions of the hepatitis C virus NS3/NS4A serine protease are studied using the second-order Møller-Plesset ab initio method and rather large basis sets to correct the previously reported AM1/CHARMM22 potential energy surfaces. The reaction efficiencies measured for the different substrates are explained in terms of the tetrahedral intermediate formation step (the rate-limiting process). The energies of the barrier and the corresponding intermediate are so close that the possibility of a concerted mechanism is open (especially for the NS5A/5B substrate). This is in contrast to the suggested general reaction mechanism of serine proteases, where a two-step mechanism is postulated.
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
Acceleration of Semiempirical QM/MM Methods through Message Passage Interface (MPI), Hybrid MPI/Open Multiprocessing, and Self-Consistent Field Accelerator Implementations.

PubMed

Ojeda-May, Pedro; Nam, Kwangho

2017-08-08

The strategy and implementation of scalable and efficient semiempirical (SE) QM/MM methods in CHARMM are described. The serial version of the code was first profiled to identify routines that required parallelization. Afterward, the code was parallelized and accelerated with three approaches. The first approach was the parallelization of the entire QM/MM routines, including the Fock matrix diagonalization routines, using the CHARMM message passage interface (MPI) machinery. In the second approach, two different self-consistent field (SCF) energy convergence accelerators were implemented using density and Fock matrices as targets for their extrapolations in the SCF procedure. In the third approach, the entire QM/MM and MM energy routines were accelerated by implementing the hybrid MPI/open multiprocessing (OpenMP) model in which both the task- and loop-level parallelization strategies were adopted to balance loads between different OpenMP threads. The present implementation was tested on two solvated enzyme systems (including <100 QM atoms) and an S N 2 symmetric reaction in water. The MPI version exceeded existing SE QM methods in CHARMM, which include the SCC-DFTB and SQUANTUM methods, by at least 4-fold. The use of SCF convergence accelerators further accelerated the code by ∼12-35% depending on the size of the QM region and the number of CPU cores used. Although the MPI version displayed good scalability, the performance was diminished for large numbers of MPI processes due to the overhead associated with MPI communications between nodes. This issue was partially overcome by the hybrid MPI/OpenMP approach which displayed a better scalability for a larger number of CPU cores (up to 64 CPUs in the tested systems).
Multiple Conformational States Contribute to the 3D Structure of a Glucan Decasaccharide: A Combined SAXS and MD Simulation Study.

PubMed

Jo, Sunhwan; Myatt, Daniel; Qi, Yifei; Doutch, James; Clifton, Luke A; Im, Wonpil; Widmalm, Göran

2018-01-25

The inherent flexibility of carbohydrates is dependent on stereochemical arrangements, and characterization of their influence and importance will give insight into the three-dimensional structure and dynamics. In this study, a β-(1→4)/β-(1→3)-linked glucosyl decasaccharide is experimentally investigated by synchrotron small-angle X-ray scattering from which its radius of gyration (R g ) is obtained. Molecular dynamics (MD) simulations of the decasaccharide show four populated states at each glycosidic linkage, namely, syn- and anti-conformations. The calculated R g values from the MD simulation reveal that in addition to syn-conformers the presence of anti-ψ conformational states is required to reproduce experimental scattering data, unveiling inherent glycosidic linkage flexibility. The CHARMM36 force field for carbohydrates thus describes the conformational flexibility of the decasaccharide very well and captures the conceptual importance that anti-conformers are to be anticipated at glycosidic linkages of carbohydrates.

Differential Impact of the Monovalent Ions Li+, Na+, K+, and Rb+ on DNA Conformational Properties

PubMed Central

2015-01-01

The present report demonstrates that the conformational properties of DNA in solution are sensitive to the type of monovalent ion. Results are based on the ability of a polarizable force field using the classical Drude oscillator to reproduce experimental solution X-ray scattering data more accurately than two nonpolarizable DNA models, AMBER Parmbsc0 and CHARMM36. The polarizable model is then used to calculate scattering profiles of DNA in the presence of four different monovalent salts, LiCl, NaCl, KCl, and RbCl, showing the conformational properties of DNA to vary as a function of ion type, with that effect being sequence-dependent. The primary conformational mode associated with the variations is contraction of the DNA minor groove width with decreasing cation size. These results indicate that the Drude polarizable model provides a more realistic representation of ion–DNA interactions than additive models that may lead to a new level of understanding of the physical mechanisms driving salt-mediated biological processes involving nucleic acids. PMID:25580188
DelPhi Web Server: A comprehensive online suite for electrostatic calculations of biological macromolecules and their complexes

PubMed Central

Sarkar, Subhra; Witham, Shawn; Zhang, Jie; Zhenirovskyy, Maxim; Rocchia, Walter; Alexov, Emil

2011-01-01

Here we report a web server, the DelPhi web server, which utilizes DelPhi program to calculate electrostatic energies and the corresponding electrostatic potential and ionic distributions, and dielectric map. The server provides extra services to fix structural defects, as missing atoms in the structural file and allows for generation of missing hydrogen atoms. The hydrogen placement and the corresponding DelPhi calculations can be done with user selected force field parameters being either Charmm22, Amber98 or OPLS. Upon completion of the calculations, the user is given option to download fixed and protonated structural file, together with the parameter and Delphi output files for further analysis. Utilizing Jmol viewer, the user can see the corresponding structural file, to manipulate it and to change the presentation. In addition, if the potential map is requested to be calculated, the potential can be mapped onto the molecule surface. The DelPhi web server is available from http://compbio.clemson.edu/delphi_webserver. PMID:24683424
Towards molecular modeling of the impact of heparin-derived oligosaccharides on hIFN-γ binding

NASA Astrophysics Data System (ADS)

Lilkova, E.; Petkov, P.; Ilieva, N.; Litov, L.

2015-10-01

Human interferon gamma (hIFN-γ) is an important signalling molecule, which plays a key role in the formation and modulation of immune response. The role of the cytokine C-termini in the formation of a complex with the extracellular receptor is still controversial due to the lack of structural information about this domain. Moreover, the C-termini are also responsible for the high affinity interaction of hIFN-γ with the glycosaminoglicans heparan sulfate and heparin. This interaction can drastically change the properties and behaviour of the protein. We performed molecular dynamics simulations in order to model the structure of the hIFN-γ C-terminal part and the interaction of the cytokine with heparin-derived oligosaccharides. For this purpose we reconstructed the missing C-terminal amino acid residues and performed folding simulations to determine their conformation. In order to simulate the interaction with heparin-like fragments, we developed CHARMM 36 compatible force field for the sulfamate anion group that is present in the glucosamine sugar to complete the heparin and heparan sulfate force field. The new topology and parameters reproduce the available experimental structural properties of heparin-like fragments. The simulations show that the oligosaccharides quickly bind the IFN-γ C-termini and reduce their solvent accessible surface area.
High quality NMR structures: a new force field with implicit water and membrane solvation for Xplor-NIH.

PubMed

Tian, Ye; Schwieters, Charles D; Opella, Stanley J; Marassi, Francesca M

2017-01-01

Structure determination of proteins by NMR is unique in its ability to measure restraints, very accurately, in environments and under conditions that closely mimic those encountered in vivo. For example, advances in solid-state NMR methods enable structure determination of membrane proteins in detergent-free lipid bilayers, and of large soluble proteins prepared by sedimentation, while parallel advances in solution NMR methods and optimization of detergent-free lipid nanodiscs are rapidly pushing the envelope of the size limit for both soluble and membrane proteins. These experimental advantages, however, are partially squandered during structure calculation, because the commonly used force fields are purely repulsive and neglect solvation, Van der Waals forces and electrostatic energy. Here we describe a new force field, and updated energy functions, for protein structure calculations with EEFx implicit solvation, electrostatics, and Van der Waals Lennard-Jones forces, in the widely used program Xplor-NIH. The new force field is based primarily on CHARMM22, facilitating calculations with a wider range of biomolecules. The new EEFx energy function has been rewritten to enable OpenMP parallelism, and optimized to enhance computation efficiency. It implements solvation, electrostatics, and Van der Waals energy terms together, thus ensuring more consistent and efficient computation of the complete nonbonded energy lists. Updates in the related python module allow detailed analysis of the interaction energies and associated parameters. The new force field and energy function work with both soluble proteins and membrane proteins, including those with cofactors or engineered tags, and are very effective in situations where there are sparse experimental restraints. Results obtained for NMR-restrained calculations with a set of five soluble proteins and five membrane proteins show that structures calculated with EEFx have significant improvements in accuracy, precision, and conformation, and that structure refinement can be obtained by short relaxation with EEFx to obtain improvements in these key metrics. These developments broaden the range of biomolecular structures that can be calculated with high fidelity from NMR restraints.
Protein structure refinement using a quantum mechanics-based chemical shielding predictor.

PubMed

Bratholm, Lars A; Jensen, Jan H

2017-03-01

The accurate prediction of protein chemical shifts using a quantum mechanics (QM)-based method has been the subject of intense research for more than 20 years but so far empirical methods for chemical shift prediction have proven more accurate. In this paper we show that a QM-based predictor of a protein backbone and CB chemical shifts (ProCS15, PeerJ , 2016, 3, e1344) is of comparable accuracy to empirical chemical shift predictors after chemical shift-based structural refinement that removes small structural errors. We present a method by which quantum chemistry based predictions of isotropic chemical shielding values (ProCS15) can be used to refine protein structures using Markov Chain Monte Carlo (MCMC) simulations, relating the chemical shielding values to the experimental chemical shifts probabilistically. Two kinds of MCMC structural refinement simulations were performed using force field geometry optimized X-ray structures as starting points: simulated annealing of the starting structure and constant temperature MCMC simulation followed by simulated annealing of a representative ensemble structure. Annealing of the CHARMM structure changes the CA-RMSD by an average of 0.4 Å but lowers the chemical shift RMSD by 1.0 and 0.7 ppm for CA and N. Conformational averaging has a relatively small effect (0.1-0.2 ppm) on the overall agreement with carbon chemical shifts but lowers the error for nitrogen chemical shifts by 0.4 ppm. If an amino acid specific offset is included the ProCS15 predicted chemical shifts have RMSD values relative to experiments that are comparable to popular empirical chemical shift predictors. The annealed representative ensemble structures differ in CA-RMSD relative to the initial structures by an average of 2.0 Å, with >2.0 Å difference for six proteins. In four of the cases, the largest structural differences arise in structurally flexible regions of the protein as determined by NMR, and in the remaining two cases, the large structural change may be due to force field deficiencies. The overall accuracy of the empirical methods are slightly improved by annealing the CHARMM structure with ProCS15, which may suggest that the minor structural changes introduced by ProCS15-based annealing improves the accuracy of the protein structures. Having established that QM-based chemical shift prediction can deliver the same accuracy as empirical shift predictors we hope this can help increase the accuracy of related approaches such as QM/MM or linear scaling approaches or interpreting protein structural dynamics from QM-derived chemical shift.
Detailed analysis of grid-based molecular docking: A case study of CDOCKER-A CHARMm-based MD docking algorithm.

PubMed

Wu, Guosheng; Robertson, Daniel H; Brooks, Charles L; Vieth, Michal

2003-10-01

The influence of various factors on the accuracy of protein-ligand docking is examined. The factors investigated include the role of a grid representation of protein-ligand interactions, the initial ligand conformation and orientation, the sampling rate of the energy hyper-surface, and the final minimization. A representative docking method is used to study these factors, namely, CDOCKER, a molecular dynamics (MD) simulated-annealing-based algorithm. A major emphasis in these studies is to compare the relative performance and accuracy of various grid-based approximations to explicit all-atom force field calculations. In these docking studies, the protein is kept rigid while the ligands are treated as fully flexible and a final minimization step is used to refine the docked poses. A docking success rate of 74% is observed when an explicit all-atom representation of the protein (full force field) is used, while a lower accuracy of 66-76% is observed for grid-based methods. All docking experiments considered a 41-member protein-ligand validation set. A significant improvement in accuracy (76 vs. 66%) for the grid-based docking is achieved if the explicit all-atom force field is used in a final minimization step to refine the docking poses. Statistical analysis shows that even lower-accuracy grid-based energy representations can be effectively used when followed with full force field minimization. The results of these grid-based protocols are statistically indistinguishable from the detailed atomic dockings and provide up to a sixfold reduction in computation time. For the test case examined here, improving the docking accuracy did not necessarily enhance the ability to estimate binding affinities using the docked structures. Copyright 2003 Wiley Periodicals, Inc.
Amino acid analogues bind to carbon nanotube via π-π interactions: Comparison of molecular mechanical and quantum mechanical calculations

NASA Astrophysics Data System (ADS)

Yang, Zaixing; Wang, Zhigang; Tian, Xingling; Xiu, Peng; Zhou, Ruhong

2012-01-01

Understanding the interaction between carbon nanotubes (CNTs) and biomolecules is essential to the CNT-based nanotechnology and biotechnology. Some recent experiments have suggested that the π-π stacking interactions between protein's aromatic residues and CNTs might play a key role in their binding, which raises interest in large scale modeling of protein-CNT complexes and associated π-π interactions at atomic detail. However, there is concern on the accuracy of classical fixed-charge molecular force fields due to their classical treatments and lack of polarizability. Here, we study the binding of three aromatic residue analogues (mimicking phenylalanine, tyrosine, and tryptophan) and benzene to a single-walled CNT, and compare the molecular mechanical (MM) calculations using three popular fixed-charge force fields (OPLSAA, AMBER, and CHARMM), with quantum mechanical (QM) calculations using the density-functional tight-binding method with the inclusion of dispersion correction (DFTB-D). Two typical configurations commonly found in π-π interactions are used, one with the aromatic rings parallel to the CNT surface (flat), and the other perpendicular (edge). Our calculations reveal that compared to the QM results the MM approaches can appropriately reproduce the strength of π-π interactions for both configurations, and more importantly, the energy difference between them, indicating that the various contributions to π-π interactions have been implicitly included in the van der Waals parameters of the standard MM force fields. Meanwhile, these MM models are less accurate in predicting the exact structural binding patterns (matching surface), meaning there are still rooms to be improved. In addition, we have provided a comprehensive and reliable QM picture for the π-π interactions of aromatic molecules with CNTs in gas phase, which might be used as a benchmark for future force field developments.
Amino acid analogues bind to carbon nanotube via π-π interactions: comparison of molecular mechanical and quantum mechanical calculations.

PubMed

Yang, Zaixing; Wang, Zhigang; Tian, Xingling; Xiu, Peng; Zhou, Ruhong

2012-01-14

Understanding the interaction between carbon nanotubes (CNTs) and biomolecules is essential to the CNT-based nanotechnology and biotechnology. Some recent experiments have suggested that the π-π stacking interactions between protein's aromatic residues and CNTs might play a key role in their binding, which raises interest in large scale modeling of protein-CNT complexes and associated π-π interactions at atomic detail. However, there is concern on the accuracy of classical fixed-charge molecular force fields due to their classical treatments and lack of polarizability. Here, we study the binding of three aromatic residue analogues (mimicking phenylalanine, tyrosine, and tryptophan) and benzene to a single-walled CNT, and compare the molecular mechanical (MM) calculations using three popular fixed-charge force fields (OPLSAA, AMBER, and CHARMM), with quantum mechanical (QM) calculations using the density-functional tight-binding method with the inclusion of dispersion correction (DFTB-D). Two typical configurations commonly found in π-π interactions are used, one with the aromatic rings parallel to the CNT surface (flat), and the other perpendicular (edge). Our calculations reveal that compared to the QM results the MM approaches can appropriately reproduce the strength of π-π interactions for both configurations, and more importantly, the energy difference between them, indicating that the various contributions to π-π interactions have been implicitly included in the van der Waals parameters of the standard MM force fields. Meanwhile, these MM models are less accurate in predicting the exact structural binding patterns (matching surface), meaning there are still rooms to be improved. In addition, we have provided a comprehensive and reliable QM picture for the π-π interactions of aromatic molecules with CNTs in gas phase, which might be used as a benchmark for future force field developments.
DOE Office of Scientific and Technical Information (OSTI.GOV)

de Hatten, Xavier; Cournia, Zoe; Huc, Ivan

The increasing importance of hydrogenase enzymes in the new energy research field has led us to examine the structure and dynamics of potential hydrogenase mimics, based on a ferrocene-peptide scaffold, using molecular dynamics (MD) simulations. To enable this MD study, a molecular mechanics force field for ferrocene-bearing peptides was developed and implemented in the CHARMM simulation package, thus extending the usefulness of the package into peptide-bioorganometallic chemistry. Using the automated frequency-matching method (AFMM), optimized intramolecular force-field parameters were generated through quantum chemical reference normal modes. The partial charges for ferrocene were derived by fitting point charges to quantum-chemically computed electrostaticmore » potentials. The force field was tested against experimental X-ray crystal structures of dipeptide derivatives of ferrocene-1,1'-dicarboxylic acid. The calculations reproduce accurately the molecular geometries, including the characteristic C{sub 2}-symmetrical intramolecular hydrogen-bonding pattern, that were stable over 0.1 {micro}s MD simulations. The crystal packing properties of ferrocene-1-(D)alanine-(D)proline-1'-(D)alanine-(D)proline were also accurately reproduced. The lattice parameters of this crystal were conserved during a 0.1 {micro}s MD simulation and match the experimental values almost exactly. Simulations of the peptides in dichloromethane are also in good agreement with experimental NMR and circular dichroism (CD) data in solution. The developed force field was used to perform MD simulations on novel, as yet unsynthesized peptide fragments that surround the active site of [Ni-Fe] hydrogenase. The results of this simulation lead us to propose an improved design for synthetic peptide-based hydrogenase models. The presented MD simulation results of metallocenes thereby provide a convincing validation of our proposal to use ferrocene-peptides as minimal enzyme mimics.« less
DOE Office of Scientific and Technical Information (OSTI.GOV)

De Hatten, Xavier; Cournia, Zoe; Smith, Jeremy C

The increasing importance of hydrogenase enzymes in the new energy research field has led us to examine the structure and dynamics of potential hydrogenase mimics, based on a ferrocene-peptide scaffold, using molecular dynamics (MD) simulations. To enable this MD study, a molecular mechanics force field for ferrocene-bearing peptides was developed and implemented in the CHARMM simulation package, thus extending the usefulness of the package into peptide-bioorganometallic chemistry. Using the automated frequency-matching method (AFMM), optimized intramolecular force-field parameters were generated through quantum chemical reference normal modes. The partial charges for ferrocene were derived by fitting point charges to quantum-chemically computed electrostaticmore » potentials. The force field was tested against experimental X-ray crystal structures of dipeptide derivatives of ferrocene-1,1{prime}-dicarboxylic acid. The calculations reproduce accurately the molecular geometries, including the characteristic C2-symmetrical intramolecular hydrogen-bonding pattern, that were stable over 0.1{micro}s MD simulations. The crystal packing properties of ferrocene-1-(D)alanine-(D)proline{prime}-1-(D)alanine-(D)proline were also accurately reproduced. The lattice parameters of this crystal were conserved during a 0.1 s MD simulation and match the experimental values almost exactly. Simulations of the peptides in dichloromethane are also in good agreement with experimental NMR and circular dichroism (CD) data in solution. The developed force field was used to perform MD simulations on novel, as yet unsynthesized peptide fragments that surround the active site of [Ni-Fe] hydrogenase. The results of this simulation lead us to propose an improved design for synthetic peptide-based hydrogenase models. The presented MD simulation results of metallocenes thereby provide a convincing validation of our proposal to use ferrocene-peptides as minimal enzyme mimics.« less
Comparison of simulation and experimental results for a model aqueous tert-butanol solution

NASA Astrophysics Data System (ADS)

Overduin, S. D.; Patey, G. N.

2017-07-01

Molecular dynamics simulations are used to investigate the behavior of aqueous tert-butanol (TBA) solutions for a range of temperatures, using the CHARMM generalized force field (CGenFF) to model TBA and the TIP4P/2005 or TIP4P-Ew water model. Simulation results for the density, isothermal compressibility, constant pressure heat capacity, and self-diffusion coefficients are in good accord with experimental measurements. Agreement with the experiment is particularly good at low TBA concentration, where experiments have revealed anomalies in a number of thermodynamic properties. Importantly, the CGenFF model does not exhibit liquid-liquid demixing at temperatures between 290 and 320 K (for systems of 32 000 molecules), in contrast with the situation for several other common TBA models [R. Gupta and G. N. Patey, J. Chem. Phys. 137, 034509 (2012)]. However, whereas real water and TBA are miscible at all temperatures where the liquid is stable, we observe some evidence of demixing at 340 K and above. To evaluate the structural properties at low concentrations, we compare with both neutron scattering and recent spectroscopic measurements. This reveals that while the CGenFF model is a definite improvement over other models that have been considered, the TBA molecules still exhibit a tendency to associate at low concentrations that is somewhat stronger than that indicated by experiments. Finally, we discuss the range and decay times of the long-range correlations, providing an indication of the system size and simulation times that are necessary in order to obtain reliable results for certain properties.
Atomistic Models of General Anesthetics for Use in in Silico Biological Studies

PubMed Central

2015-01-01

While small molecules have been used to induce anesthesia in a clinical setting for well over a century, a detailed understanding of the molecular mechanism remains elusive. In this study, we utilize ab initio calculations to develop a novel set of CHARMM-compatible parameters for the ubiquitous modern anesthetics desflurane, isoflurane, sevoflurane, and propofol for use in molecular dynamics (MD) simulations. The parameters generated were rigorously tested against known experimental physicochemical properties including dipole moment, density, enthalpy of vaporization, and free energy of solvation. In all cases, the anesthetic parameters were able to reproduce experimental measurements, signifying the robustness and accuracy of the atomistic models developed. The models were then used to study the interaction of anesthetics with the membrane. Calculation of the potential of mean force for inserting the molecules into a POPC bilayer revealed a distinct energetic minimum of 4–5 kcal/mol relative to aqueous solution at the level of the glycerol backbone in the membrane. The location of this minimum within the membrane suggests that anesthetics partition to the membrane prior to binding their ion channel targets, giving context to the Meyer–Overton correlation. Moreover, MD simulations of these drugs in the membrane give rise to computed membrane structural parameters, including atomic distribution, deuterium order parameters, dipole potential, and lateral stress profile, that indicate partitioning of anesthetics into the membrane at the concentration range studied here, which does not appear to perturb the structural integrity of the lipid bilayer. These results signify that an indirect, membrane-mediated mechanism of channel modulation is unlikely. PMID:25303275
Structural Ensemble of CD4 Cytoplasmic Tail (402-419) Reveals a Nearly Flat Free-Energy Landscape with Local α-Helical Order in Aqueous Solution.

PubMed

Ahalawat, Navjeet; Arora, Simran; Murarka, Rajesh K

2015-08-27

The human cluster determinant 4 (CD4), expressed primarily on the surface of T helper cells, serves as a coreceptor in T-cell receptor recognition of MHC II antigen complexes. Besides its cellular functions, CD4 serves as a primary receptor of human immunodeficiency virus (HIV) type 1. The cytoplasmic tail of CD4 (residues 402-419) is known to be involved in direct interaction with the HIV-1 proteins Vpu and Nef. These two viral accessory proteins (Vpu and Nef) downregulate CD4 in HIV-1 infected cells by multiple strategies and make the body susceptible to all forms of infections. In this work, we carried out extensive replica exchange molecular dynamics simulations in explicit water with three popular protein force fields Amber ff99SB, Amber ff99SB*-ILDN, and CHARMM36 to characterize the equilibrium conformational ensemble of CD4-tail (402-419) and further validated the simulated ensembles with known NMR data. We found that ff99SB*-ILDN gives a better description of the structural ensemble of this peptide compared with ff99SB and CHARMM36. The peptide adopts multiple distinct conformations with varying degree of residual secondary structures. In particular, we observed 28, 7, and 5% average α-helical, β-strand, and 3(10)-helix content, respectively, for ff99SB*-ILDN. The peptide chain shows the tendency of helix formation in a cooperative manner, seeding at residues 407-410, and subsequently extending toward both ends of the chain. Furthermore, we constructed Markov state model (MSM) from large-scale molecular dynamics simulations to study the dynamics of transitions between different metastable states explored by this peptide. The mean first passage times computed from MSM indicate rapid interconversion of these states, and the time scales of transitions range from several nanoseconds to hundreds of microseconds. Our results show good agreement with experimental data and could help to understand the key molecular mechanisms of T-cell activation and HIV-mediated receptor interference.
Molecular dynamics simulation studies of caffeine aggregation in aqueous solution.

PubMed

Tavagnacco, Letizia; Schnupf, Udo; Mason, Philip E; Saboungi, Marie-Louise; Cesàro, Attilio; Brady, John W

2011-09-22

Molecular dynamics simulations were carried out on a system of eight independent caffeine molecules in a periodic box of water at 300 K, representing a solution near the solubility limit for caffeine at room temperature, using a newly developed CHARMM-type force field for caffeine in water. Simulations were also conducted for single caffeine molecules in water using two different water models (TIP3P and TIP4P). Water was found to structure in a complex fashion around the planar caffeine molecules, which was not sensitive to the water model used. As expected, extensive aggregation of the caffeine molecules was observed, with the molecules stacking their flat faces against one another like coins, with their methylene groups staggered to avoid steric clashes. A dynamic equilibrum was observed between large n-mers, including stacks with all eight solute molecules, and smaller clusters, with the calculated osmotic coefficient being in acceptable agreement with the experimental value. The insensitivity of the results to water model and the congruence with experimental thermodynamic data suggest that the observed stacking interactions are a realistic representation of the actual association mechanism in aqueous caffeine solutions.
Understanding the EF-hand closing pathway using non-biased interatomic potentials.

PubMed

Dupuis, L; Mousseau, Normand

2012-01-21

The EF-hand superfamily of proteins is characterized by the presence of calcium binding helix-loop-helix structures. Many of these proteins undergo considerable motion responsible for a wide range of properties upon binding but the exact mechanism at the root of this motion is not fully understood. Here, we use an unbiased accelerated multiscale simulation scheme, coupled with two force fields - CHARMM-EEF1 and the extended OPEP - to explore in details the closing pathway, from the unbound holo state to the closed apo state, of two EF-hand proteins, the Calmodulin and Troponin C N-terminal nodules. Based on a number of closing simulations for these two sequences, we show that the EF-hand β-scaffold, identified as crucial by Grabarek for the EF-hand opening driven by calcium binding, is also important in closing the EF-hand. We also show the crucial importance of the phenylalanine situated at the end of first EF-hand helix, and identify an intermediate state modulating its behavior, providing a detailed picture of the closing mechanism for these two representatives of EF-hand proteins. © 2012 American Institute of Physics
Protein structure refinement using a quantum mechanics-based chemical shielding predictor† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c6sc04344e Click here for additional data file.

PubMed Central

2017-01-01

The accurate prediction of protein chemical shifts using a quantum mechanics (QM)-based method has been the subject of intense research for more than 20 years but so far empirical methods for chemical shift prediction have proven more accurate. In this paper we show that a QM-based predictor of a protein backbone and CB chemical shifts (ProCS15, PeerJ, 2016, 3, e1344) is of comparable accuracy to empirical chemical shift predictors after chemical shift-based structural refinement that removes small structural errors. We present a method by which quantum chemistry based predictions of isotropic chemical shielding values (ProCS15) can be used to refine protein structures using Markov Chain Monte Carlo (MCMC) simulations, relating the chemical shielding values to the experimental chemical shifts probabilistically. Two kinds of MCMC structural refinement simulations were performed using force field geometry optimized X-ray structures as starting points: simulated annealing of the starting structure and constant temperature MCMC simulation followed by simulated annealing of a representative ensemble structure. Annealing of the CHARMM structure changes the CA-RMSD by an average of 0.4 Å but lowers the chemical shift RMSD by 1.0 and 0.7 ppm for CA and N. Conformational averaging has a relatively small effect (0.1–0.2 ppm) on the overall agreement with carbon chemical shifts but lowers the error for nitrogen chemical shifts by 0.4 ppm. If an amino acid specific offset is included the ProCS15 predicted chemical shifts have RMSD values relative to experiments that are comparable to popular empirical chemical shift predictors. The annealed representative ensemble structures differ in CA-RMSD relative to the initial structures by an average of 2.0 Å, with >2.0 Å difference for six proteins. In four of the cases, the largest structural differences arise in structurally flexible regions of the protein as determined by NMR, and in the remaining two cases, the large structural change may be due to force field deficiencies. The overall accuracy of the empirical methods are slightly improved by annealing the CHARMM structure with ProCS15, which may suggest that the minor structural changes introduced by ProCS15-based annealing improves the accuracy of the protein structures. Having established that QM-based chemical shift prediction can deliver the same accuracy as empirical shift predictors we hope this can help increase the accuracy of related approaches such as QM/MM or linear scaling approaches or interpreting protein structural dynamics from QM-derived chemical shift. PMID:28451325
De novo protein structure prediction by dynamic fragment assembly and conformational space annealing.

PubMed

Lee, Juyong; Lee, Jinhyuk; Sasaki, Takeshi N; Sasai, Masaki; Seok, Chaok; Lee, Jooyoung

2011-08-01

Ab initio protein structure prediction is a challenging problem that requires both an accurate energetic representation of a protein structure and an efficient conformational sampling method for successful protein modeling. In this article, we present an ab initio structure prediction method which combines a recently suggested novel way of fragment assembly, dynamic fragment assembly (DFA) and conformational space annealing (CSA) algorithm. In DFA, model structures are scored by continuous functions constructed based on short- and long-range structural restraint information from a fragment library. Here, DFA is represented by the full-atom model by CHARMM with the addition of the empirical potential of DFIRE. The relative contributions between various energy terms are optimized using linear programming. The conformational sampling was carried out with CSA algorithm, which can find low energy conformations more efficiently than simulated annealing used in the existing DFA study. The newly introduced DFA energy function and CSA sampling algorithm are implemented into CHARMM. Test results on 30 small single-domain proteins and 13 template-free modeling targets of the 8th Critical Assessment of protein Structure Prediction show that the current method provides comparable and complementary prediction results to existing top methods. Copyright © 2011 Wiley-Liss, Inc.
Efficient implementation of constant pH molecular dynamics on modern graphics processors.

PubMed

Arthur, Evan J; Brooks, Charles L

2016-09-15

The treatment of pH sensitive ionization states for titratable residues in proteins is often omitted from molecular dynamics (MD) simulations. While static charge models can answer many questions regarding protein conformational equilibrium and protein-ligand interactions, pH-sensitive phenomena such as acid-activated chaperones and amyloidogenic protein aggregation are inaccessible to such models. Constant pH molecular dynamics (CPHMD) coupled with the Generalized Born with a Simple sWitching function (GBSW) implicit solvent model provide an accurate framework for simulating pH sensitive processes in biological systems. Although this combination has demonstrated success in predicting pKa values of protein structures, and in exploring dynamics of ionizable side-chains, its speed has been an impediment to routine application. The recent availability of low-cost graphics processing unit (GPU) chipsets with thousands of processing cores, together with the implementation of the accurate GBSW implicit solvent model on those chipsets (Arthur and Brooks, J. Comput. Chem. 2016, 37, 927), provide an opportunity to improve the speed of CPHMD and ionization modeling greatly. Here, we present a first implementation of GPU-enabled CPHMD within the CHARMM-OpenMM simulation package interface. Depending on the system size and nonbonded force cutoff parameters, we find speed increases of between one and three orders of magnitude. Additionally, the algorithm scales better with system size than the CPU-based algorithm, thus allowing for larger systems to be modeled in a cost effective manner. We anticipate that the improved performance of this methodology will open the door for broad-spread application of CPHMD in its modeling pH-mediated biological processes. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Structure of aqueous proline via parallel tempering molecular dynamics and neutron diffraction.

PubMed

Troitzsch, R Z; Martyna, G J; McLain, S E; Soper, A K; Crain, J

2007-07-19

The structure of aqueous L-proline amino acid has been the subject of much debate centering on the validity of various proposed models, differing widely in the extent to which local and long-range correlations are present. Here, aqueous proline is investigated by atomistic, replica exchange molecular dynamics simulations, and the results are compared to neutron diffraction and small angle neutron scattering (SANS) data, which have been reported recently (McLain, S.; Soper, A.; Terry, A.; Watts, A. J. Phys. Chem. B 2007, 111, 4568). Comparisons between neutron experiments and simulation are made via the static structure factor S(Q) which is measured and computed from several systems with different H/D isotopic compositions at a concentration of 1:20 molar ratio. Several different empirical water models (TIP3P, TIP4P, and SPC/E) in conjunction with the CHARMM22 force field are investigated. Agreement between experiment and simulation is reasonably good across the entire Q range although there are significant model-dependent variations in some cases. In general, agreement is improved slightly upon application of approximate quantum corrections obtained from gas-phase path integral simulations. Dimers and short oligomeric chains formed by hydrogen bonds (frequently bifurcated) coexist with apolar (hydrophobic) contacts. These emerge as the dominant local motifs in the mixture. Evidence for long-range association is more equivocal: No long-range structures form spontaneously in the MD simulations, and no obvious low-Q signature is seen in the SANS data. Moreover, associations introduced artificially to replicate a long-standing proposed mesoscale structure for proline correlations as an initial condition are annealed out by parallel tempering MD simulations. However, some small residual aggregates do remain, implying a greater degree of long-range order than is apparent in the SANS data.
Reconciling Structural and Thermodynamic Predictions Using All-Atom and Coarse-Grain Force Fields: The Case of Charged Oligo-Arginine Translocation into DMPC Bilayers

PubMed Central

2015-01-01

Using the translocation of short, charged cationic oligo-arginine peptides (mono-, di-, and triarginine) from bulk aqueous solution into model DMPC bilayers, we explore the question of the similarity of thermodynamic and structural predictions obtained from molecular dynamics simulations using all-atom and Martini coarse-grain force fields. Specifically, we estimate potentials of mean force associated with translocation using standard all-atom (CHARMM36 lipid) and polarizable and nonpolarizable Martini force fields, as well as a series of modified Martini-based parameter sets. We find that we are able to reproduce qualitative features of potentials of mean force of single amino acid side chain analogues into model bilayers. In particular, modifications of peptide–water and peptide–membrane interactions allow prediction of free energy minima at the bilayer–water interface as obtained with all-atom force fields. In the case of oligo-arginine peptides, the modified parameter sets predict interfacial free energy minima as well as free energy barriers in almost quantitative agreement with all-atom force field based simulations. Interfacial free energy minima predicted by a modified coarse-grained parameter set are −2.51, −4.28, and −5.42 for mono-, di-, and triarginine; corresponding values from all-atom simulations are −0.83, −3.33, and −3.29, respectively, all in units of kcal/mol. We found that a stronger interaction between oligo-arginine and the membrane components and a weaker interaction between oligo-arginine and water are crucial for producing such minima in PMFs using the polarizable CG model. The difference between bulk aqueous and bilayer center states predicted by the modified coarse-grain force field are 11.71, 14.14, and 16.53 kcal/mol, and those by the all-atom model are 6.94, 8.64, and 12.80 kcal/mol; those are of almost the same order of magnitude. Our simulations also demonstrate a remarkable similarity in the structural aspects of the ensemble of configurations generated using the all-atom and coarse-grain force fields. Both resolutions show that oligo-arginine peptides adopt preferential orientations as they translocate into the bilayer. The guiding theme centers on charged groups maintaining coordination with polar and charged bilayer components as well as local water. We also observe similar behaviors related with membrane deformations. PMID:25290376

Reconciling structural and thermodynamic predictions using all-atom and coarse-grain force fields: the case of charged oligo-arginine translocation into DMPC bilayers.

PubMed

Hu, Yuan; Sinha, Sudipta Kumar; Patel, Sandeep

2014-10-16

Using the translocation of short, charged cationic oligo-arginine peptides (mono-, di-, and triarginine) from bulk aqueous solution into model DMPC bilayers, we explore the question of the similarity of thermodynamic and structural predictions obtained from molecular dynamics simulations using all-atom and Martini coarse-grain force fields. Specifically, we estimate potentials of mean force associated with translocation using standard all-atom (CHARMM36 lipid) and polarizable and nonpolarizable Martini force fields, as well as a series of modified Martini-based parameter sets. We find that we are able to reproduce qualitative features of potentials of mean force of single amino acid side chain analogues into model bilayers. In particular, modifications of peptide-water and peptide-membrane interactions allow prediction of free energy minima at the bilayer-water interface as obtained with all-atom force fields. In the case of oligo-arginine peptides, the modified parameter sets predict interfacial free energy minima as well as free energy barriers in almost quantitative agreement with all-atom force field based simulations. Interfacial free energy minima predicted by a modified coarse-grained parameter set are -2.51, -4.28, and -5.42 for mono-, di-, and triarginine; corresponding values from all-atom simulations are -0.83, -3.33, and -3.29, respectively, all in units of kcal/mol. We found that a stronger interaction between oligo-arginine and the membrane components and a weaker interaction between oligo-arginine and water are crucial for producing such minima in PMFs using the polarizable CG model. The difference between bulk aqueous and bilayer center states predicted by the modified coarse-grain force field are 11.71, 14.14, and 16.53 kcal/mol, and those by the all-atom model are 6.94, 8.64, and 12.80 kcal/mol; those are of almost the same order of magnitude. Our simulations also demonstrate a remarkable similarity in the structural aspects of the ensemble of configurations generated using the all-atom and coarse-grain force fields. Both resolutions show that oligo-arginine peptides adopt preferential orientations as they translocate into the bilayer. The guiding theme centers on charged groups maintaining coordination with polar and charged bilayer components as well as local water. We also observe similar behaviors related with membrane deformations.
Computing the Rotational Diffusion of Biomolecules via Molecular Dynamics Simulation and Quaternion Orientations.

PubMed

Chen, Po-Chia; Hologne, Maggy; Walker, Olivier

2017-03-02

Rotational diffusion (D rot ) is a fundamental property of biomolecules that contains information about molecular dimensions and solute-solvent interactions. While ab initio D rot prediction can be achieved by explicit all-atom molecular dynamics simulations, this is hindered by both computational expense and limitations in water models. We propose coarse-grained force fields as a complementary solution, and show that the MARTINI force field with elastic networks is sufficient to compute D rot in >10 proteins spanning 5-157 kDa. We also adopt a quaternion-based approach that computes D rot orientation directly from autocorrelations of best-fit rotations as used in, e.g., RMSD algorithms. Over 2 μs trajectories, isotropic MARTINI+EN tumbling replicates experimental values to within 10-20%, with convergence analyses suggesting a minimum sampling of >50 × τ theor to achieve sufficient precision. Transient fluctuations in anisotropic tumbling cause decreased precision in predictions of axisymmetric anisotropy and rhombicity, the latter of which cannot be precisely evaluated within 2000 × τ theor for GB3. Thus, we encourage reporting of axial decompositions D x , D y , D z to ease comparability between experiment and simulation. Where protein disorder is absent, we observe close replication of MARTINI+EN D rot orientations versus CHARMM22*/TIP3p and experimental data. This work anticipates the ab initio prediction of NMR-relaxation by combining coarse-grained global motions with all-atom local motions.
Application of advanced sampling and analysis methods to predict the structure of adsorbed protein on a material surface

PubMed Central

Abramyan, Tigran M.; Hyde-Volpe, David L.; Stuart, Steven J.; Latour, Robert A.

2017-01-01

The use of standard molecular dynamics simulation methods to predict the interactions of a protein with a material surface have the inherent limitations of lacking the ability to determine the most likely conformations and orientations of the adsorbed protein on the surface and to determine the level of convergence attained by the simulation. In addition, standard mixing rules are typically applied to combine the nonbonded force field parameters of the solution and solid phases the system to represent interfacial behavior without validation. As a means to circumvent these problems, the authors demonstrate the application of an efficient advanced sampling method (TIGER2A) for the simulation of the adsorption of hen egg-white lysozyme on a crystalline (110) high-density polyethylene surface plane. Simulations are conducted to generate a Boltzmann-weighted ensemble of sampled states using force field parameters that were validated to represent interfacial behavior for this system. The resulting ensembles of sampled states were then analyzed using an in-house-developed cluster analysis method to predict the most probable orientations and conformations of the protein on the surface based on the amount of sampling performed, from which free energy differences between the adsorbed states were able to be calculated. In addition, by conducting two independent sets of TIGER2A simulations combined with cluster analyses, the authors demonstrate a method to estimate the degree of convergence achieved for a given amount of sampling. The results from these simulations demonstrate that these methods enable the most probable orientations and conformations of an adsorbed protein to be predicted and that the use of our validated interfacial force field parameter set provides closer agreement to available experimental results compared to using standard CHARMM force field parameterization to represent molecular behavior at the interface. PMID:28514864
Antimicrobial Peptide Simulations and the Influence of Force Field on the Free Energy for Pore Formation in Lipid Bilayers.

PubMed

Bennett, W F Drew; Hong, Chun Kit; Wang, Yi; Tieleman, D Peter

2016-09-13

Due to antimicrobial resistance, the development of new drugs to combat bacterial and fungal infections is an important area of research. Nature uses short, charged, and amphipathic peptides for antimicrobial defense, many of which disrupt the lipid membrane in addition to other possible targets inside the cell. Computer simulations have revealed atomistic details for the interactions of antimicrobial peptides and cell-penetrating peptides with lipid bilayers. Strong interactions between the polar interface and the charged peptides can induce bilayer deformations - including membrane rupture and peptide stabilization of a hydrophilic pore. Here, we performed microsecond-long simulations of the antimicrobial peptide CM15 in a POPC bilayer expecting to observe pore formation (based on previous molecular dynamics simulations). We show that caution is needed when interpreting results of equilibrium peptide-membrane simulations, given the length of time single trajectories can dwell in local energy minima for 100's of ns to microseconds. While we did record significant membrane perturbations from the CM15 peptide, pores were not observed. We explain this discrepancy by computing the free energy for pore formation with different force fields. Our results show a large difference in the free energy barrier (ca. 40 kJ/mol) against pore formation predicted by the different force fields that would result in orders of magnitude differences in the simulation time required to observe spontaneous pore formation. This explains why previous simulations using the Berger lipid parameters reported pores induced by charged peptides, while with CHARMM based models pores were not observed in our long time-scale simulations. We reconcile some of the differences in the distance dependent free energies by shifting the free energy profiles to account for thickness differences between force fields. The shifted curves show that all the models describe small defects in lipid bilayers in a consistent manner, suggesting a common physical basis.
Atomistic Simulations of the pH Induced Functional Rearrangement of Influenza Hemagglutinin

NASA Astrophysics Data System (ADS)

Lin, Xingcheng; Noel, Jeffrey; Wang, Qinghua; Ma, Jianpeng; Onuchic, Jose

Influenza hemagglutinin (HA), a surface glycoprotein responsible for the entry and replication of flu viruses in their host cells, functions by starting a dramatic conformational rearrangement, which leads to a fusion of the viral and endosomal membranes. It has been claimed that a loop-to-coiled-coil transition of the B-loop domain of HA drives the HA-induced membrane fusion. On the lack of dynamical details, however, the microscopic picture for this proposed ``spring-loaded'' movement is missing. To elaborate on the transition of the B-loop, we performed a set of unbiased all-atom molecular dynamics simulations of the full B-loop structure with the CHARMM36 force field. The complete free-energy profile constructed from our simulations reveals a slow transition rate for the B-loop that is incompatible with a downhill process. Additionally, our simulations indicate two potential sources of kinetic traps in the structural switch of the B-loop: Desolvation barriers and non-native secondary structure formation. The slow timescale of the B-loop transition also confirms our previous discovery from simulations using a coarse-grained structure-based model, which identified two competitive pathways both with a slow B-loop transition for HA to guide the membrane fusion.
Bayesian energy landscape tilting: towards concordant models of molecular ensembles.

PubMed

Beauchamp, Kyle A; Pande, Vijay S; Das, Rhiju

2014-03-18

Predicting biological structure has remained challenging for systems such as disordered proteins that take on myriad conformations. Hybrid simulation/experiment strategies have been undermined by difficulties in evaluating errors from computational model inaccuracies and data uncertainties. Building on recent proposals from maximum entropy theory and nonequilibrium thermodynamics, we address these issues through a Bayesian energy landscape tilting (BELT) scheme for computing Bayesian hyperensembles over conformational ensembles. BELT uses Markov chain Monte Carlo to directly sample maximum-entropy conformational ensembles consistent with a set of input experimental observables. To test this framework, we apply BELT to model trialanine, starting from disagreeing simulations with the force fields ff96, ff99, ff99sbnmr-ildn, CHARMM27, and OPLS-AA. BELT incorporation of limited chemical shift and (3)J measurements gives convergent values of the peptide's α, β, and PPII conformational populations in all cases. As a test of predictive power, all five BELT hyperensembles recover set-aside measurements not used in the fitting and report accurate errors, even when starting from highly inaccurate simulations. BELT's principled framework thus enables practical predictions for complex biomolecular systems from discordant simulations and sparse data. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Molecular Dynamics Simulation Studies of Caffeine Aggregation in Aqueous Solution

PubMed Central

Tavagnacco, Letizia; Schnupf, Udo; Mason, Philip E.; Saboungi, Marie-Louise; Cesàro, Attilio; Brady, John W.

2011-01-01

Molecular dynamics simulations were carried out on a system of eight independent caffeine molecules in a periodic box of water at 300 K, representing a solution near the solubility limit for caffeine at room temperature, using a newly-developed CHARMM-type force field for caffeine in water. Simulations were also conducted for single caffeine molecules in water using two different water models (TIP3P and TIP4P). Water was found to structure in a complex fashion around the planar caffeine molecules, which was not sensitive to the water model used. As expected, extensive aggregation of the caffeine molecules was observed, with the molecules stacking their flat faces against one another like coins, with their methylene groups staggered to avoid steric clashes. A dynamic equilibrum was observed between large n-mers, including stacks with all eight solute molecules, and smaller clusters, with the calculated osmotic coefficient being in acceptable agreement with the experimental value. The insensitivity of the results to water model and the congruence with experimental thermodynamic data suggest that the observed stacking interactions are a realistic representation of the actual association mechanism in aqueous caffeine solutions. PMID:21812485
Genetic Algorithms and Their Application to the Protein Folding Problem

DTIC Science & Technology

1993-12-01

and symbolic methods, random methods such as Monte Carlo simulation and simulated annealing, distance geometry, and molecular dynamics. Many of these...calculated energies with those obtained using the molecular simulation software package called CHARMm. 10 9) Test both the simple and parallel simpie genetic...homology-based, and simplification techniques. 3.21 Molecular Dynamics. Perhaps the most natural approach is to actually simulate the folding process. This
GENESIS 1.1: A hybrid-parallel molecular dynamics simulator with enhanced sampling algorithms on multiple computational platforms.

PubMed

Kobayashi, Chigusa; Jung, Jaewoon; Matsunaga, Yasuhiro; Mori, Takaharu; Ando, Tadashi; Tamura, Koichi; Kamiya, Motoshi; Sugita, Yuji

2017-09-30

GENeralized-Ensemble SImulation System (GENESIS) is a software package for molecular dynamics (MD) simulation of biological systems. It is designed to extend limitations in system size and accessible time scale by adopting highly parallelized schemes and enhanced conformational sampling algorithms. In this new version, GENESIS 1.1, new functions and advanced algorithms have been added. The all-atom and coarse-grained potential energy functions used in AMBER and GROMACS packages now become available in addition to CHARMM energy functions. The performance of MD simulations has been greatly improved by further optimization, multiple time-step integration, and hybrid (CPU + GPU) computing. The string method and replica-exchange umbrella sampling with flexible collective variable choice are used for finding the minimum free-energy pathway and obtaining free-energy profiles for conformational changes of a macromolecule. These new features increase the usefulness and power of GENESIS for modeling and simulation in biological research. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
LOOS: an extensible platform for the structural analysis of simulations.

PubMed

Romo, Tod D; Grossfield, Alan

2009-01-01

We have developed LOOS (Lightweight Object-Oriented Structure-analysis library) as an object-oriented library designed to facilitate the rapid development of tools for the structural analysis of simulations. LOOS supports the native file formats of most common simulation packages including AMBER, CHARMM, CNS, Gromacs, NAMD, Tinker, and X-PLOR. Encapsulation and polymorphism are used to simultaneously provide a stable interface to the programmer and make LOOS easily extensible. A rich atom selection language based on the C expression syntax is included as part of the library. LOOS enables students and casual programmer-scientists to rapidly write their own analytical tools in a compact and expressive manner resembling scripting. LOOS is written in C++ and makes extensive use of the Standard Template Library and Boost, and is freely available under the GNU General Public License (version 3) LOOS has been tested on Linux and MacOS X, but is written to be portable and should work on most Unix-based platforms.
Efficient simulations of the aqueous bio-interface of graphitic nanostructures with a polarisable model

NASA Astrophysics Data System (ADS)

Hughes, Zak E.; Tomásio, Susana M.; Walsh, Tiffany R.

2014-04-01

To fully harness the enormous potential offered by interfaces between graphitic nanostructures and biomolecules, detailed connections between adsorbed conformations and adsorption behaviour are needed. To elucidate these links, a key approach, in partnership with experimental techniques, is molecular simulation. For this, a force-field (FF) that can appropriately capture the relevant physics and chemistry of these complex bio-interfaces, while allowing extensive conformational sampling, and also supporting inter-operability with known biological FFs, is a pivotal requirement. Here, we present and apply such a force-field, GRAPPA, designed to work with the CHARMM FF. GRAPPA is an efficiently implemented polarisable force-field, informed by extensive plane-wave DFT calculations using the revPBE-vdW-DF functional. GRAPPA adequately recovers the spatial and orientational structuring of the aqueous interface of graphene and carbon nanotubes, compared with more sophisticated approaches. We apply GRAPPA to determine the free energy of adsorption for a range of amino acids, identifying Trp, Tyr and Arg to have the strongest binding affinity and Asp to be a weak binder. The GRAPPA FF can be readily incorporated into mainstream simulation packages, and will enable large-scale polarisable biointerfacial simulations at graphitic interfaces, that will aid the development of biomolecule-mediated, solution-based graphene processing and self-assembly strategies.To fully harness the enormous potential offered by interfaces between graphitic nanostructures and biomolecules, detailed connections between adsorbed conformations and adsorption behaviour are needed. To elucidate these links, a key approach, in partnership with experimental techniques, is molecular simulation. For this, a force-field (FF) that can appropriately capture the relevant physics and chemistry of these complex bio-interfaces, while allowing extensive conformational sampling, and also supporting inter-operability with known biological FFs, is a pivotal requirement. Here, we present and apply such a force-field, GRAPPA, designed to work with the CHARMM FF. GRAPPA is an efficiently implemented polarisable force-field, informed by extensive plane-wave DFT calculations using the revPBE-vdW-DF functional. GRAPPA adequately recovers the spatial and orientational structuring of the aqueous interface of graphene and carbon nanotubes, compared with more sophisticated approaches. We apply GRAPPA to determine the free energy of adsorption for a range of amino acids, identifying Trp, Tyr and Arg to have the strongest binding affinity and Asp to be a weak binder. The GRAPPA FF can be readily incorporated into mainstream simulation packages, and will enable large-scale polarisable biointerfacial simulations at graphitic interfaces, that will aid the development of biomolecule-mediated, solution-based graphene processing and self-assembly strategies. Electronic supplementary information (ESI) available: Details of the testing of four different DFT functionals; the adsorption energies and separation distances for the full set of analogue molecules; details of the adsorption energies of the phenyl species on the graphene surface at different adsorption sites; snapshots of the set-ups of the three different water-graphene simulations; plane-wave DFT minimum energy configurations of the full set of analogue molecules; details of the development and parametrisation of the GRAPPA FF; details of the parameters and setup used for the AMEOBAPRO simulations; the probability distribution of the O-H bond vectors of water molecules at the graphene interface; details of the simulation times for the (14 × 0) CNT systems using the different FFs; details of tests performed to determine the contribution of polarisability to binding energies; the RMSD between the reference values and plane-wave DFT values of different groups of molecules; 2D density maps of water on the graphene interface; density and hydrogen bond profiles for the simulations of water inside CNTs; 2D density maps of water inside the CNTs; plots of the collective variable against time for the meta-dynamics simulations; probability distributions of the angle between the plane of the aromatic rings and the graphene surface; the probability distribution of distance of the methyl carbon from the graphene surface for Ala. See DOI: 10.1039/c4nr00468j
Influence of Polarization on Carbohydrate Hydration: A Comparative Study Using Additive and Polarizable Force Fields.

PubMed

Pandey, Poonam; Mallajosyula, Sairam S

2016-07-14

Carbohydrates are known to closely modulate their surrounding solvent structures and influence solvation dynamics. Spectroscopic investigations studying far-IR regions (below 1000 cm(-1)) have observed spectral shifts in the libration band (around 600 cm(-1)) of water in the presence of monosaccharides and polysaccharides. In this paper, we use molecular dynamics simulations to gain atomistic insight into carbohydrate-water interactions and to specifically highlight the differences between additive (nonpolarizable) and polarizable simulations. A total of six monosaccharide systems, α and β anomers of glucose, galactose, and mannose, were studied using additive and polarizable Chemistry at HARvard Macromolecular Mechanics (CHARMM) carbohydrate force fields. Solvents were modeled using three additive water models TIP3P, TIP4P, and TIP5P in additive simulations and polarizable water model SWM4 in polarizable simulations. The presence of carbohydrate has a significant effect on the microscopic water structure, with the effects being pronounced for proximal water molecules. Notably, disruption of the tetrahedral arrangement of proximal water molecules was observed due to the formation of strong carbohydrate-water hydrogen bonds in both additive and polarizable simulations. However, the inclusion of polarization resulted in significant water-bridge occupancies, improved ordered water structures (tetrahedral order parameter), and longer carbohydrate-water H-bond correlations as compared to those for additive simulations. Additionally, polarizable simulations also allowed the calculation of power spectra from the dipole-dipole autocorrelation function, which corresponds to the IR spectra. From the power spectra, we could identify spectral signatures differentiating the proximal and bulk water structures, which could not be captured from additive simulations.
Comparative Study of the Collective Dynamics of Proteins and Inorganic Nanoparticles

PubMed Central

Haddadian, Esmael J.; Zhang, Hao; Freed, Karl F.; Douglas, Jack F.

2017-01-01

Molecular dynamics simulations of ubiquitin in water/glycerol solutions are used to test the suggestion by Karplus and coworkers that proteins in their biologically active state should exhibit a dynamics similar to ‘surface-melted’ inorganic nanoparticles (NPs). Motivated by recent studies indicating that surface-melted inorganic NPs are in a ‘glassy’ state that is an intermediate dynamical state between a solid and liquid, we probe the validity and significance of this proposed analogy. In particular, atomistic simulations of ubiquitin in solution based on CHARMM36 force field and pre-melted Ni NPs (Voter-Chen Embedded Atom Method potential) indicate a common dynamic heterogeneity, along with other features of glass-forming (GF) liquids such as collective atomic motion in the form of string-like atomic displacements, potential energy fluctuations and particle displacements with long range correlations (‘colored’ or ‘pink’ noise), and particle displacement events having a power law scaling in magnitude, as found in earthquakes. On the other hand, we find the dynamics of ubiquitin to be even more like a polycrystalline material in which the α-helix and β-sheet regions of the protein are similar to crystal grains so that the string-like collective atomic motion is concentrated in regions between the α-helix and β-sheet domains. PMID:28176808
Molecular dynamics studies of polyethylene oxide and polyethylene glycol: hydrodynamic radius and shape anisotropy.

PubMed

Lee, Hwankyu; Venable, Richard M; Mackerell, Alexander D; Pastor, Richard W

2008-08-01

A revision (C35r) to the CHARMM ether force field is shown to reproduce experimentally observed conformational populations of dimethoxyethane. Molecular dynamics simulations of 9, 18, 27, and 36-mers of polyethylene oxide (PEO) and 27-mers of polyethylene glycol (PEG) in water based on C35r yield a persistence length lambda = 3.7 A, in quantitative agreement with experimentally obtained values of 3.7 A for PEO and 3.8 A for PEG; agreement with experimental values for hydrodynamic radii of comparably sized PEG is also excellent. The exponent upsilon relating the radius of gyration and molecular weight (R(g) proportional, variantM(w)(upsilon)) of PEO from the simulations equals 0.515 +/- 0.023, consistent with experimental observations that low molecular weight PEG behaves as an ideal chain. The shape anisotropy of hydrated PEO is 2.59:1.44:1.00. The dimension of the middle length for each of the polymers nearly equals the hydrodynamic radius R(h)obtained from diffusion measurements in solution. This explains the correspondence of R(h) and R(p), the pore radius of membrane channels: a polymer such as PEG diffuses with its long axis parallel to the membrane channel, and passes through the channel without substantial distortion.
Comparative Study of the Collective Dynamics of Proteins and Inorganic Nanoparticles

NASA Astrophysics Data System (ADS)

Haddadian, Esmael J.; Zhang, Hao; Freed, Karl F.; Douglas, Jack F.

2017-02-01

Molecular dynamics simulations of ubiquitin in water/glycerol solutions are used to test the suggestion by Karplus and coworkers that proteins in their biologically active state should exhibit a dynamics similar to ‘surface-melted’ inorganic nanoparticles (NPs). Motivated by recent studies indicating that surface-melted inorganic NPs are in a ‘glassy’ state that is an intermediate dynamical state between a solid and liquid, we probe the validity and significance of this proposed analogy. In particular, atomistic simulations of ubiquitin in solution based on CHARMM36 force field and pre-melted Ni NPs (Voter-Chen Embedded Atom Method potential) indicate a common dynamic heterogeneity, along with other features of glass-forming (GF) liquids such as collective atomic motion in the form of string-like atomic displacements, potential energy fluctuations and particle displacements with long range correlations (‘colored’ or ‘pink’ noise), and particle displacement events having a power law scaling in magnitude, as found in earthquakes. On the other hand, we find the dynamics of ubiquitin to be even more like a polycrystalline material in which the α-helix and β-sheet regions of the protein are similar to crystal grains so that the string-like collective atomic motion is concentrated in regions between the α-helix and β-sheet domains.
Molecular Dynamics of β-Hairpin Models of Epigenetic Recognition Motifs

PubMed Central

Zheng, Xiange; Wu, Chuanjie; Ponder, Jay W.; Marshall, Garland R.

2012-01-01

The conformations and stabilities of the β-hairpin model peptides of Waters1,2 have been experimentally characterized as a function of lysine ε-methylation. These models were developed to explore molecular recognition of known epigenetic recognition motifs. This system offered an opportunity to computationally examine the role of cation-π interactions, desolvation of the ε-methylated ammonium groups, and aromatic/aromatic interactions on the observed differences in NMR spectra. AMOEBA, a second-generation force field4, was chosen as it includes both multipole electrostatics and polarizability thought to be essential to accurately characterize such interactions. Independent parameterization of ε-methylated amines was required from which aqueous solvation free energies were estimated and shown to agree with literature values. Molecular dynamics simulations (100 ns) using the derived parameters with model peptides, such as Ac-R-W-V-W-V-N-G-Orn-K(Me)n -I-L-Q-NH2, where n = 0, 1, 2, or 3, were conducted in explicit solvent. Distances between the centers of the indole rings of the two-tryptophan residues, 2 and 4, and the ε-methylated ammonium group on Lys-9 as well as the distance between the N- and C-termini were monitored to estimate the strength and orientation of the cation-π and aromatic/aromatic interactions. In agreement with the experimental data, the stability of the β-hairpin increased significantly with lysine ε-methylation. The ability of MD simulations to reproduce the observed NOEs for the four peptides was further estimated for the monopole-based force fields, AMBER, CHARMM, and OPLSAA. AMOEBA correctly predicted over 80% of the observed NOEs for all four peptides, while the three-monopole force fields were 40–50% predictive in only two cases and approximately 10% in the other ten examples. Preliminary analysis suggests that the decreased cost of desolvation of the substituted ammonium group significantly compensated for the reduced cation-π interaction resulting from the increased separation due to steric bulk of the ε-methylated amines. PMID:22934656
Convergence and reproducibility in molecular dynamics simulations of the DNA duplex d(GCACGAACGAACGAACGC).

PubMed

Galindo-Murillo, Rodrigo; Roe, Daniel R; Cheatham, Thomas E

2015-05-01

The structure and dynamics of DNA are critically related to its function. Molecular dynamics simulations augment experiment by providing detailed information about the atomic motions. However, to date the simulations have not been long enough for convergence of the dynamics and structural properties of DNA. Molecular dynamics simulations performed with AMBER using the ff99SB force field with the parmbsc0 modifications, including ensembles of independent simulations, were compared to long timescale molecular dynamics performed with the specialized Anton MD engine on the B-DNA structure d(GCACGAACGAACGAACGC). To assess convergence, the decay of the average RMSD values over longer and longer time intervals was evaluated in addition to assessing convergence of the dynamics via the Kullback-Leibler divergence of principal component projection histograms. These molecular dynamics simulations-including one of the longest simulations of DNA published to date at ~44μs-surprisingly suggest that the structure and dynamics of the DNA helix, neglecting the terminal base pairs, are essentially fully converged on the ~1-5μs timescale. We can now reproducibly converge the structure and dynamics of B-DNA helices, omitting the terminal base pairs, on the μs time scale with both the AMBER and CHARMM C36 nucleic acid force fields. Results from independent ensembles of simulations starting from different initial conditions, when aggregated, match the results from long timescale simulations on the specialized Anton MD engine. With access to large-scale GPU resources or the specialized MD engine "Anton" it is possible for a variety of molecular systems to reproducibly and reliably converge the conformational ensemble of sampled structures. This article is part of a Special Issue entitled: Recent developments of molecular dynamics. Copyright © 2014. Published by Elsevier B.V.
T-Cell Receptors Binding Orientation over Peptide/MHC Class I Is Driven by Long-Range Interactions

PubMed Central

Ferber, Mathias; Zoete, Vincent; Michielin, Olivier

2012-01-01

Crystallographic data about T-Cell Receptor – peptide – major histocompatibility complex class I (TCRpMHC) interaction have revealed extremely diverse TCR binding modes triggering antigen recognition. Understanding the molecular basis that governs TCR orientation over pMHC is still a considerable challenge. We present a simplified rigid approach applied on all non-redundant TCRpMHC crystal structures available. The CHARMM force field in combination with the FACTS implicit solvation model is used to study the role of long-distance interactions between the TCR and pMHC. We demonstrate that the sum of the coulomb interactions and the electrostatic solvation energies is sufficient to identify two orientations corresponding to energetic minima at 0° and 180° from the native orientation. Interestingly, these results are shown to be robust upon small structural variations of the TCR such as changes induced by Molecular Dynamics simulations, suggesting that shape complementarity is not required to obtain a reliable signal. Accurate energy minima are also identified by confronting unbound TCR crystal structures to pMHC. Furthermore, we decompose the electrostatic energy into residue contributions to estimate their role in the overall orientation. Results show that most of the driving force leading to the formation of the complex is defined by CDR1,2/MHC interactions. This long-distance contribution appears to be independent from the binding process itself, since it is reliably identified without considering neither short-range energy terms nor CDR induced fit upon binding. Ultimately, we present an attempt to predict the TCR/pMHC binding mode for a TCR structure obtained by homology modeling. The simplicity of the approach and the absence of any fitted parameters make it also easily applicable to other types of macromolecular protein complexes. PMID:23251658
Simulations of simple Bovine and Homo sapiens outer cortex ocular lens membrane models with a majority concentration of cholesterol.

PubMed

Adams, Mark; Wang, Eric; Zhuang, Xiaohong; Klauda, Jeffery B

2017-11-21

The lipid composition of bovine and human ocular lens membranes has been probed, and a variety of lipids have been found including phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM), and cholesterol (CHOL) with cholesterol being present in particularly high concentrations. In this study, we use the all-atom CHARMM36 force field to simulate binary, ternary, and quaternary mixtures as models of the ocular lens. High concentration of cholesterol, in combination with different and varying diversity of phospholipids (PL) and sphingolipids (SL), affect the structure of the ocular lens lipid bilayer. The following analyses were done for each simulation: surface area per lipid, component surface area per lipid, deuterium order parameters (S CD ), electron density profiles (EDP), membrane thickness, hydrogen bonding, radial distribution functions, clustering, and sterol tilt angle distribution. The S CD show significant bilayer alignment and packing in cholesterol-rich bilayers. The EDP show the transition from liquid crystalline to liquid ordered with the addition of cholesterol. Hydrogen bonds in our systems show the tendency for intramolecular interactions between cholesterol and fully saturated lipid tails for less complex bilayers. But with an increased number of components in the bilayer, the acyl chain of the lipids becomes a less important characteristic, and the headgroup of the lipid becomes more significant. Overall, cholesterol is the driving force of membrane structure of the ocular lens membrane where interactions between cholesterol, PL, and SL determine structure and function of the biomembrane. The goal of this work is to develop a baseline for further study of more physiologically realistic ocular lens lipid membranes. This article is part of a Special Issue entitled: Emergence of Complex Behavior in Biomembranes edited by Marjorie Longo. Copyright © 2017 Elsevier B.V. All rights reserved.
T-cell receptors binding orientation over peptide/MHC class I is driven by long-range interactions.

PubMed

Ferber, Mathias; Zoete, Vincent; Michielin, Olivier

2012-01-01

Crystallographic data about T-Cell Receptor - peptide - major histocompatibility complex class I (TCRpMHC) interaction have revealed extremely diverse TCR binding modes triggering antigen recognition. Understanding the molecular basis that governs TCR orientation over pMHC is still a considerable challenge. We present a simplified rigid approach applied on all non-redundant TCRpMHC crystal structures available. The CHARMM force field in combination with the FACTS implicit solvation model is used to study the role of long-distance interactions between the TCR and pMHC. We demonstrate that the sum of the coulomb interactions and the electrostatic solvation energies is sufficient to identify two orientations corresponding to energetic minima at 0° and 180° from the native orientation. Interestingly, these results are shown to be robust upon small structural variations of the TCR such as changes induced by Molecular Dynamics simulations, suggesting that shape complementarity is not required to obtain a reliable signal. Accurate energy minima are also identified by confronting unbound TCR crystal structures to pMHC. Furthermore, we decompose the electrostatic energy into residue contributions to estimate their role in the overall orientation. Results show that most of the driving force leading to the formation of the complex is defined by CDR1,2/MHC interactions. This long-distance contribution appears to be independent from the binding process itself, since it is reliably identified without considering neither short-range energy terms nor CDR induced fit upon binding. Ultimately, we present an attempt to predict the TCR/pMHC binding mode for a TCR structure obtained by homology modeling. The simplicity of the approach and the absence of any fitted parameters make it also easily applicable to other types of macromolecular protein complexes.

Redox potential tuning through differential quinone binding in the photosynthetic reaction center of Rhodobacter sphaeroides

DOE PAGES

Vermaas, Josh V.; Taguchi, Alexander T.; Dikanov, Sergei A.; ...

2015-03-03

Ubiquinone forms an integral part of the electron transport chain in cellular respiration and photosynthesis across a vast number of organisms. Prior experimental results have shown that the photosynthetic reaction center (RC) from Rhodobacter sphaeroides is only fully functional with a limited set of methoxy-bearing quinones, suggesting that specific interactions with this substituent are required to drive electron transport and the formation of quinol. The nature of these interactions has yet to be determined. Through parameterization of a CHARMM-compatible quinone force field and subsequent molecular dynamics simulations of the quinone-bound RC, in this paper we have investigated and characterized themore » interactions of the protein with the quinones in the Q A and Q B sites using both equilibrium simulation and thermodynamic integration. In particular, we identify a specific interaction between the 2-methoxy group of ubiquinone in the Q B site and the amide nitrogen of GlyL225 that we implicate in locking the orientation of the 2-methoxy group, thereby tuning the redox potential difference between the quinones occupying the Q A and Q B sites. Finally, disruption of this interaction leads to weaker binding in a ubiquinone analogue that lacks a 2-methoxy group, a finding supported by reverse electron transfer electron paramagnetic resonance experiments of the Q A–Q B– biradical and competitive binding assays.« less
Prediction, Refinement and Persistency of Transmembrane Helix Dimers in Lipid Bilayers using Implicit and Explicit Solvent/Lipid Representations: Microsecond Molecular Dynamics Simulations of ErbB1/B2 and EphA1

PubMed Central

Zhang, Liqun; Sodt, Alexander J.; Venable, Richard M.; Pastor, Richard W.; Buck, Matthias

2012-01-01

All-atom simulations are carried out on ErbB1/B2 and EphA1 transmembrane helix dimers in lipid bilayers starting from their solution/DMPC bicelle NMR structures. Over the course of microsecond trajectories, the structures remain in close proximity to the initial configuration and satisfy the great majority of experimental tertiary contact restraints. These results further validate CHARMM protein/lipid force fields and simulation protocols on Anton. Separately, dimer conformations are generated using replica exchange in conjunction with an implicit solvent and lipid representation. The implicit model requires further improvement, and this study investigates whether lengthy all-atom molecular dynamics simulations can alleviate the shortcomings of the initial conditions. The simulations correct many of the deficiencies. For example excessive helix twisting is eliminated over a period of hundreds of nanoseconds. The helix tilt, crossing angles and dimer contacts approximate those of the NMR derived structure, although the detailed contact surface remains off-set for one of two helices in both systems. Hence, even microsecond simulations are not long enough for extensive helix rotations. The alternate structures can be rationalized with reference to interaction motifs and may represent still sought after receptor states that are important in ErbB1/B2 and EphA1 signaling. PMID:23042146
Scalable Molecular Dynamics with NAMD

PubMed Central

Phillips, James C.; Braun, Rosemary; Wang, Wei; Gumbart, James; Tajkhorshid, Emad; Villa, Elizabeth; Chipot, Christophe; Skeel, Robert D.; Kalé, Laxmikant; Schulten, Klaus

2008-01-01

NAMD is a parallel molecular dynamics code designed for high-performance simulation of large biomolecular systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This paper, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical molecular dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temperature and pressure controls used. Features for steering the simulation across barriers and for calculating both alchemical and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Next, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomolecular system, highlighting particular features of NAMD, e.g., the Tcl scripting language. Finally, the paper provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the molecular graphics/sequence analysis software VMD and the grid computing/collaboratory software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu. PMID:16222654
Simulations of simple linoleic acid-containing lipid membranes and models for the soybean plasma membranes.

PubMed

Zhuang, Xiaohong; Ou, Anna; Klauda, Jeffery B

2017-06-07

The all-atom CHARMM36 lipid force field (C36FF) has been tested with saturated, monounsaturated, and polyunsaturated lipids; however, it has not been validated against the 18:2 linoleoyl lipids with an unsaturated sn-1 chain. The linoleoyl lipids are common in plants and the main component of the soybean membrane. The lipid composition of soybean plasma membranes has been thoroughly characterized with experimental studies. However, there is comparatively less work done with computational modeling. Our molecular dynamics (MD) simulation results show that the pure linoleoyl lipids, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine (18:0/18:2) and 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (di-18:2), agree very well with the experiments, which demonstrates the accuracy of the C36FF for the computational study of soybean membranes. Based on the experimental composition, the soybean hypocotyl and root plasma membrane models are developed with each containing seven or eight types of linoleoyl phospholipids and two types of sterols (sitosterol and stigmasterol). MD simulations are performed to characterize soybean membranes, and the hydrogen bonds and clustering results demonstrate that the lipids prefer to interact with the lipids of the same/similar tail unsaturation. All the results suggest that these two soybean membrane models can be used as a basis for further research in soybean and higher plant membranes involving membrane-associated proteins.
Effect of Membrane Tension on the Electric Field and Dipole Potential of Lipid Bilayer Membrane

PubMed Central

Warshaviak, Dora Toledo; Muellner, Michael J.; Chachisvilis, Mirianas

2011-01-01

The dipole potential of lipid bilayer membrane controls the difference in permeability of the membrane to oppositely charged ions. We have combined molecular dynamics (MD) simulations and experimental studies to determine changes in electric field and electrostatic potential of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid bilayer in response to applied membrane tension. MD simulations based on CHARMM36 force field showed that electrostatic potential of DOPC bilayer decreases by ~45 mV in the physiologically relevant range of membrane tension values (0 to 15 dyn/cm). The electrostatic field exhibits a peak (~0.8×109 V/m) near the water/lipid interface which shifts by 0.9 Å towards the bilayer center at 15 dyn/cm. Maximum membrane tension of 15 dyn/cm caused 6.4% increase in area per lipid, 4.7% decrease in bilayer thickness and 1.4% increase in the volume of the bilayer. Dipole-potential sensitive fluorescent probes were used to detect membrane tension induced changes in DOPC vesicles exposed to osmotic stress. Experiments confirmed that dipole potential of DOPC bilayer decreases at higher membrane tensions. These results are suggestive of a potentially new mechanosensing mechanism by which mechanically induced structural changes in the lipid bilayer membrane could modulate the function of membrane proteins by altering electrostatic interactions and energetics of protein conformational states. PMID:21722624
Combined ab initio/empirical approach for optimization of Lennard-Jones parameters for polar-neutral compounds.

PubMed

Chen, I Jen; Yin, Daxu; MacKerell, Alexander D

2002-01-30

The study of small functionalized organic molecules in aqueous solution is a useful step toward gaining a basic understanding of the behavior of biomolecular systems in their native aqueous environment. Interest in studying amines and fluorine-substituted compounds has risen from their intrinsic physicochemical properties and their prevalence in biological and pharmaceutical compounds. In the present study, a previously developed approach which optimizes Lennard-Jones (LJ) parameters via the use of rare gas atoms combined with the reproduction of experimental condensed phase properties was extended to polar-neutral compounds. Compounds studied included four amines (ammonia, methylamine, dimethylamine, and trimethylamine) and three fluoroethanes (1-fluoroethane, 1,1-difluoroethane, and 1,1,1-trifluoroethane). The resulting force field yielded heats of vaporization and molecular volumes in excellent agreement with the experiment, with average differences less than 1%. The current amine CHARMM parameters successfully reproduced experimental aqueous solvation data where methylamine is more hydrophilic than ammonia, with hydrophobicity increasing with additional methylation on the nitrogen. For both the amines and fluoroethanes the parabolic relationship of the extent of methylation or fluorination, respectively, to the heats of vaporization were reproduced by the new parameters. The present results are also discussed with respect to the impact of parameterization approach to molecular details obtained from computer simulations and to the unique biological properties of fluorine in pharmaceutical compounds.
Molecular dynamic of curcumin/chitosan interaction using a computational molecular approach: Emphasis on biofilm reduction.

PubMed

Khezri, Azam; Karimi, Arsalan; Yazdian, Fatemeh; Jokar, Mahmoud; Mofradnia, Soheil Rezazadeh; Rashedi, Hamid; Tavakoli, Zahra

2018-07-15

Nanotechnology-based drug delivery systems have been used to enhance bioavailability and biological activities. Chitosan incorporating curcumin can serve as a biocompatible substitute for metallic nanoparticles in preventing biofilm formation of Streptococcus mutans and plaque on teeth. The interactions between chitosan nanoparticle as a carrier and curcumin, a natural antibacterial agent, were simulated. The binding conformation between curcumin-chitosan was obtained using the Lamarckian Genetic Algorithm in Autodock™ software in chitosan nanoparticle. The interaction stability was examined in the molecular dynamic stages, with isothermal-isobaric ensemble in the CHARMM Force Field. The results showed the root mean square deviation (RMSD) and the root mean square fluctuations (RMSF) for all complex's atoms were relaxed after 4ns (RMSD for the all-atoms was 26.81±0.1 (Å); RMSF 1.13±0.02Å). For each section, the estimation of RMSD, RMSF, radius of gyration, inter-H bond and other analysis confirmed that, during the first interval;10ns, there was a stable binding between the two sections. Although all bindings disappeared from 10 to 20ns, the curcumin was trapped inside the chitosan nanoparticles, and no release took place until 20ns, after which the curcumin began to release. This trend suggests that chitosan nanoparticle has ability to carry the curcumin. Copyright © 2018 Elsevier B.V. All rights reserved.
Redox potential tuning through differential quinone binding in the photosynthetic reaction center of Rhodobacter sphaeroides.

PubMed

Vermaas, Josh V; Taguchi, Alexander T; Dikanov, Sergei A; Wraight, Colin A; Tajkhorshid, Emad

2015-03-31

Ubiquinone forms an integral part of the electron transport chain in cellular respiration and photosynthesis across a vast number of organisms. Prior experimental results have shown that the photosynthetic reaction center (RC) from Rhodobacter sphaeroides is only fully functional with a limited set of methoxy-bearing quinones, suggesting that specific interactions with this substituent are required to drive electron transport and the formation of quinol. The nature of these interactions has yet to be determined. Through parameterization of a CHARMM-compatible quinone force field and subsequent molecular dynamics simulations of the quinone-bound RC, we have investigated and characterized the interactions of the protein with the quinones in the Q(A) and Q(B) sites using both equilibrium simulation and thermodynamic integration. In particular, we identify a specific interaction between the 2-methoxy group of ubiquinone in the Q(B) site and the amide nitrogen of GlyL225 that we implicate in locking the orientation of the 2-methoxy group, thereby tuning the redox potential difference between the quinones occupying the Q(A) and Q(B) sites. Disruption of this interaction leads to weaker binding in a ubiquinone analogue that lacks a 2-methoxy group, a finding supported by reverse electron transfer electron paramagnetic resonance experiments of the Q(A)⁻Q(B)⁻ biradical and competitive binding assays.
Simulations of simple linoleic acid-containing lipid membranes and models for the soybean plasma membranes

NASA Astrophysics Data System (ADS)

Zhuang, Xiaohong; Ou, Anna; Klauda, Jeffery B.

2017-06-01

The all-atom CHARMM36 lipid force field (C36FF) has been tested with saturated, monounsaturated, and polyunsaturated lipids; however, it has not been validated against the 18:2 linoleoyl lipids with an unsaturated sn-1 chain. The linoleoyl lipids are common in plants and the main component of the soybean membrane. The lipid composition of soybean plasma membranes has been thoroughly characterized with experimental studies. However, there is comparatively less work done with computational modeling. Our molecular dynamics (MD) simulation results show that the pure linoleoyl lipids, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine (18:0/18:2) and 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (di-18:2), agree very well with the experiments, which demonstrates the accuracy of the C36FF for the computational study of soybean membranes. Based on the experimental composition, the soybean hypocotyl and root plasma membrane models are developed with each containing seven or eight types of linoleoyl phospholipids and two types of sterols (sitosterol and stigmasterol). MD simulations are performed to characterize soybean membranes, and the hydrogen bonds and clustering results demonstrate that the lipids prefer to interact with the lipids of the same/similar tail unsaturation. All the results suggest that these two soybean membrane models can be used as a basis for further research in soybean and higher plant membranes involving membrane-associated proteins.
Long Dynamics Simulations of Proteins Using Atomistic Force Fields and a Continuum Representation of Solvent Effects: Calculation of Structural and Dynamic Properties

PubMed Central

Li, Xianfeng; Hassan, Sergio A.; Mehler, Ernest L.

2006-01-01

Long dynamics simulations were carried out on the B1 immunoglobulin-binding domain of streptococcal protein G (ProtG) and bovine pancreatic trypsin inhibitor (BPTI) using atomistic descriptions of the proteins and a continuum representation of solvent effects. To mimic frictional and random collision effects, Langevin dynamics (LD) were used. The main goal of the calculations was to explore the stability of tens-of-nanosecond trajectories as generated by this molecular mechanics approximation and to analyze in detail structural and dynamical properties. Conformational fluctuations, order parameters, cross correlation matrices, residue solvent accessibilities, pKa values of titratable groups, and hydrogen-bonding (HB) patterns were calculated from all of the trajectories and compared with available experimental data. The simulations comprised over 40 ns per trajectory for ProtG and over 30 ns per trajectory for BPTI. For comparison, explicit water molecular dynamics simulations (EW/MD) of 3 ns and 4 ns, respectively, were also carried out. Two continuum simulations were performed on each protein using the CHARMM program, one with the all-atom PAR22 representation of the protein force field (here referred to as PAR22/LD simulations) and the other with the modifications introduced by the recently developed CMAP potential (CMAP/LD simulations). The explicit solvent simulations were performed with PAR22 only. Solvent effects are described by a continuum model based on screened Coulomb potentials (SCP) reported earlier, i.e., the SCP-based implicit solvent model (SCP–ISM). For ProtG, both the PAR22/LD and the CMAP/LD 40-ns trajectories were stable, yielding Cα root mean square deviations (RMSD) of about 1.0 and 0.8 Å respectively along the entire simulation time, compared to 0.8 Å for the EW/MD simulation. For BPTI, only the CMAP/LD trajectory was stable for the entire 30-ns simulation, with a Cα RMSD of ≈ 1.4 Å, while the PAR22/LD trajectory became unstable early in the simulation, reaching a Cα RMSD of about 2.7 Å and remaining at this value until the end of the simulation; the Cα RMSD of the EW/MD simulation was about 1.5 Å. The source of the instabilities of the BPTI trajectories in the PAR22/LD simulations was explored by an analysis of the backbone torsion angles. To further validate the findings from this analysis of BPTI, a 35-ns SCP–ISM simulation of Ubiquitin (Ubq) was carried out. For this protein, the CMAP/LD simulation was stable for the entire simulation time (Cα RMSD of ≈1.0 Å), while the PAR22/LD trajectory showed a trend similar to that in BPTI, reaching a Cα RMSD of ≈1.5 Å at 7 ns. All the calculated properties were found to be in agreement with the corresponding experimental values, although local deviations were also observed. HB patterns were also well reproduced by all the continuum solvent simulations with the exception of solvent-exposed side chain–side chain (sc–sc) HB in ProtG, where several of the HB interactions observed in the crystal structure and in the EW/MD simulation were lost. The overall analysis reported in this work suggests that the combination of an atomistic representation of a protein with a CMAP/CHARMM force field and a continuum representation of solvent effects such as the SCP–ISM provides a good description of structural and dynamic properties obtained from long computer simulations. Although the SCP–ISM simulations (CMAP/LD) reported here were shown to be stable and the properties well reproduced, further refinement is needed to attain a level of accuracy suitable for more challenging biological applications, particularly the study of protein–protein interactions. PMID:15959866
Web-Based Computational Chemistry Education with CHARMMing II: Coarse-Grained Protein Folding

PubMed Central

Schalk, Vinushka; Lerner, Michael G.; Woodcock, H. Lee; Brooks, Bernard R.

2014-01-01

A lesson utilizing a coarse-grained (CG) G-like model has been implemented into the CHARMM INterface and Graphics (CHARMMing) web portal (www.charmming.org) to the Chemistry at HARvard Macromolecular Mechanics (CHARMM) molecular simulation package. While widely used to model various biophysical processes, such as protein folding and aggregation, CG models can also serve as an educational tool because they can provide qualitative descriptions of complex biophysical phenomena for a relatively cheap computational cost. As a proof of concept, this lesson demonstrates the construction of a CG model of a small globular protein, its simulation via Langevin dynamics, and the analysis of the resulting data. This lesson makes connections between modern molecular simulation techniques and topics commonly presented in an advanced undergraduate lecture on physical chemistry. It culminates in a straightforward analysis of a short dynamics trajectory of a small fast folding globular protein; we briefly describe the thermodynamic properties that can be calculated from this analysis. The assumptions inherent in the model and the data analysis are laid out in a clear, concise manner, and the techniques used are consistent with those employed by specialists in the field of CG modeling. One of the major tasks in building the G-like model is determining the relative strength of the nonbonded interactions between coarse-grained sites. New functionality has been added to CHARMMing to facilitate this process. The implementation of these features into CHARMMing helps automate many of the tedious aspects of constructing a CG G model. The CG model builder and its accompanying lesson should be a valuable tool to chemistry students, teachers, and modelers in the field. PMID:25058338
Web-based computational chemistry education with CHARMMing II: Coarse-grained protein folding.

PubMed

Pickard, Frank C; Miller, Benjamin T; Schalk, Vinushka; Lerner, Michael G; Woodcock, H Lee; Brooks, Bernard R

2014-07-01

A lesson utilizing a coarse-grained (CG) Gō-like model has been implemented into the CHARMM INterface and Graphics (CHARMMing) web portal (www.charmming.org) to the Chemistry at HARvard Macromolecular Mechanics (CHARMM) molecular simulation package. While widely used to model various biophysical processes, such as protein folding and aggregation, CG models can also serve as an educational tool because they can provide qualitative descriptions of complex biophysical phenomena for a relatively cheap computational cost. As a proof of concept, this lesson demonstrates the construction of a CG model of a small globular protein, its simulation via Langevin dynamics, and the analysis of the resulting data. This lesson makes connections between modern molecular simulation techniques and topics commonly presented in an advanced undergraduate lecture on physical chemistry. It culminates in a straightforward analysis of a short dynamics trajectory of a small fast folding globular protein; we briefly describe the thermodynamic properties that can be calculated from this analysis. The assumptions inherent in the model and the data analysis are laid out in a clear, concise manner, and the techniques used are consistent with those employed by specialists in the field of CG modeling. One of the major tasks in building the Gō-like model is determining the relative strength of the nonbonded interactions between coarse-grained sites. New functionality has been added to CHARMMing to facilitate this process. The implementation of these features into CHARMMing helps automate many of the tedious aspects of constructing a CG Gō model. The CG model builder and its accompanying lesson should be a valuable tool to chemistry students, teachers, and modelers in the field.
High level QM/MM modeling of the formation of the tetrahedral intermediate in the acylation of wild type and K73A mutant TEM-1 class A beta-lactamase.

PubMed

Hermann, Johannes C; Pradon, Juliette; Harvey, Jeremy N; Mulholland, Adrian J

2009-10-29

The breakdown of beta-lactam antibiotics by beta-lactamases is the most important resistance mechanism of gram negative bacteria against these drugs. The reaction mechanism of class A beta-lactamases, the most widespread family of these enzymes, consists of two main steps: acylation of an active site serine by the antibiotic, followed by deacylation and release of the cleaved compound. We have investigated the first step in acylation (the formation of the tetrahedral intermediate) for the reaction of benzylpenicillin in the TEM-1 enzyme using high level combined quantum mechanics/molecular mechanics (QM/MM) methods. Structures were optimized at the B3LYP/6-31+G(d)/CHARMM27 level, with energies for key points calculated up to the ab initio SCS-MP2/aug-cc-pVTZ/CHARMM27 level. The results support a mechanism in which Glu166 removes a proton (via an intervening water molecule) from Ser70, which in turn attacks the beta-lactam of the antibiotic. Depending on the method used, the calculated barriers range from 3 to 12 kcal mol(-1) for this step, consistent with experimental data. We have also modeled this reaction step in a model of the K73A mutant enzyme. The barrier to reaction in this mutant model is found to be slightly higher: the results indicate that Lys73 stabilizes the transition state, in particular deprotonated Ser70, lowering the barrier by about 1.7 kcal mol(-1). This finding may help to explain the conservation of Lys73, in addition to the role we have previously found for it in the later stages of the reaction (Hermann et al. Org. Biomol. Chem. 2006, 4, 206-210).
Determinants of reactivity and selectivity in soluble epoxide hydrolase from quantum mechanics/molecular mechanics modeling.

PubMed

Lonsdale, Richard; Hoyle, Simon; Grey, Daniel T; Ridder, Lars; Mulholland, Adrian J

2012-02-28

Soluble epoxide hydrolase (sEH) is an enzyme involved in drug metabolism that catalyzes the hydrolysis of epoxides to form their corresponding diols. sEH has a broad substrate range and shows high regio- and enantioselectivity for nucleophilic ring opening by Asp333. Epoxide hydrolases therefore have potential synthetic applications. We have used combined quantum mechanics/molecular mechanics (QM/MM) umbrella sampling molecular dynamics (MD) simulations (at the AM1/CHARMM22 level) and high-level ab initio (SCS-MP2) QM/MM calculations to analyze the reactions, and determinants of selectivity, for two substrates: trans-stilbene oxide (t-SO) and trans-diphenylpropene oxide (t-DPPO). The calculated free energy barriers from the QM/MM (AM1/CHARMM22) umbrella sampling MD simulations show a lower barrier for phenyl attack in t-DPPO, compared with that for benzylic attack, in agreement with experiment. Activation barriers in agreement with experimental rate constants are obtained only with the highest level of QM theory (SCS-MP2) used. Our results show that the selectivity of the ring-opening reaction is influenced by several factors, including proximity to the nucleophile, electronic stabilization of the transition state, and hydrogen bonding to two active site tyrosine residues. The protonation state of His523 during nucleophilic attack has also been investigated, and our results show that the protonated form is most consistent with experimental findings. The work presented here illustrates how determinants of selectivity can be identified from QM/MM simulations. These insights may also provide useful information for the design of novel catalysts for use in the synthesis of enantiopure compounds.
High Level QM/MM Modeling of the Formation of the Tetrahedral Intermediate in the Acylation of Wild Type and K73A Mutant TEM-1 Class A β-Lactamase

NASA Astrophysics Data System (ADS)

Hermann, Johannes C.; Pradon, Juliette; Harvey, Jeremy N.; Mulholland, Adrian J.

2009-09-01

The breakdown of β-lactam antibiotics by β-lactamases is the most important resistance mechanism of Gram negative bacteria against these drugs. The reaction mechanism of class A β-lactamases, the most widespread family of these enzymes, consists of two main steps: acylation of an active site serine by the antibiotic, followed by deacylation and release of the cleaved compound. We have investigated the first step in acylation (the formation of the tetrahedral intermediate) for the reaction of benzylpenicillin in the TEM-1 enzyme using high level combined quantum mechanics/molecular mechanics (QM/MM) methods. Structures were optimized at the B3LYP/6-31+G(d)/CHARMM27 level, with energies for key points calculated up to the ab initio SCS-MP2/aug-cc-pVTZ/CHARMM27 level. The results support a mechanism in which Glu166 removes a proton (via an intervening water molecule) from Ser70, which in turn attacks the β-lactam of the antibiotic. Depending on the method used, the calculated barriers range from 3 to 12 kcal mol-1 for this step, consistent with experimental data. We have also modeled this reaction step in a model of the K73A mutant enzyme. The barrier to reaction in this mutant model is found to be slightly higher: the results indicate that Lys73 stabilizes the transition state, in particular deprotonated Ser70, lowering the barrier by about 1.7 kcal mol-1. This finding may help to explain the conservation of Lys73, in addition to the role we have previously found for it in the later stages of the reaction ( Hermann et al. Org. Biomol. Chem. 2006, 4, 206 - 210 ).
Simulaid: a simulation facilitator and analysis program.

PubMed

Mezei, Mihaly

2010-11-15

Simulaid performs a large number of simulation-related tasks: interconversion and modification of structure and trajectory files, optimization of orientation, and a large variety of analysis functions. The program can handle structures in PDB (Berman et al., Nucleic Acids Res 2000, 28, 235), Charmm (Brooks et al., J Comput Chem 4, 187) CRD, Amber (Case et al.), Macromodel (Mohamadi et al., J Comput Chem 1990, 11, 440), Gromos/Gromacs (Hess et al.), InsightII (InsightII. Accelrys Inc.: San Diego, 2005), Grasp (Nicholls et al., Proteins: Struct Funct Genet 1991, 11, 281) .crg, Tripos (Tripos International, S. H. R., St. Louis, MO) .mol2 (input only), and in the MMC (Mezei, M.; MMC: Monte Carlo program for molecular assemblies. Available at: http://inka.mssm.edu/~mezei/mmc) formats; and trajectories in the formats of Charmm, Amber, Macromodel, and MMC. Analysis features include (but are not limited to): (1) simple distance calculations and hydrogen-bond analysis, (2) calculation of 2-D RMSD maps (produced both as text file with the data and as a color-coded matrix) and cross RMSD maps between trajectories, (3) clustering based on RMSD maps, (4) analysis of torsion angles, Ramachandran (Ramachandran and Sasiskharan, Adv Protein Chem 1968, 23, 283) angles, proline kink (Visiers et al., Protein Eng 2000, 13, 603) angles, pseudorotational (Altona and Sundaralingam, J Am Chem Soc 1972, 94, 8205; Cremer and Pople, J Am Chem Soc 1975, 97, 1354) angles, and (5) analysis based on circular variance (Mezei, J Mol Graphics Model 2003, 21, 463). Torsion angle evolutions are presented in dial plots (Ravishanker et al., J Biomol Struct Dyn 1989, 6, 669). Several of these features are unique to Simulaid. 2010 Wiley Periodicals, Inc.
Substrate polarization in enzyme catalysis: QM/MM analysis of the effect of oxaloacetate polarization on acetyl-CoA enolization in citrate synthase.

PubMed

van der Kamp, Marc W; Perruccio, Francesca; Mulholland, Adrian J

2007-11-15

Citrate synthase is an archetypal carbon-carbon bond forming enzyme. It promotes the conversion of oxaloacetate (OAA) to citrate by catalyzing the deprotonation (enolization) of acetyl-CoA, followed by nucleophilic attack of the enolate form of this substrate on OAA to form a citryl-CoA intermediate and subsequent hydrolysis. OAA is strongly bound to the active site and its alpha-carbonyl group is polarized. This polarization has been demonstrated spectroscopically, [(Kurz et al., Biochemistry 1985;24:452-457; Kurz and Drysdale, Biochemistry 1987;26:2623-2627)] and has been suggested to be an important catalytic strategy. Substrate polarization is believed to be important in many enzymes. The first step, formation of the acetyl-CoA enolate intermediate, is thought to be rate-limiting in the mesophilic (pig/chicken) enzyme. We have examined the effects of substrate polarization on this key step using quantum mechanical/molecular mechanical (QM/MM) methods. Free energy profiles have been calculated by AM1/CHARMM27 umbrella sampling molecular dynamics (MD) simulations, together with potential energy profiles. To study the influence of OAA polarization, profiles were calculated with different polarization of the OAA alpha-carbonyl group. The results indicate that OAA polarization influences catalysis only marginally but has a larger effect on intermediate stabilization. Different levels of treatment of OAA are compared (MM or QM), and its polarization in the protein and in water analyzed at the B3LYP/6-31+G(d)/CHARMM27 level. Analysis of stabilization by individual residues shows that the enzyme mainly stabilizes the enolate intermediate (not the transition state) through electrostatic (including hydrogen bond) interactions: these contribute much more than polarization of OAA. (c) 2007 Wiley-Liss, Inc.
Antioxidant and cytotoxic activity of new di- and polyamine caffeine analogues.

PubMed

Jasiewicz, Beata; Sierakowska, Arleta; Jankowski, Wojciech; Hoffmann, Marcin; Piorońska, Weronika; Górnicka, Agnieszka; Bielawska, Anna; Bielawski, Krzysztof; Mrówczyńska, Lucyna

2018-04-18

A series of new di- and polyamine-caffeine analogues were synthesized and characterized by NMR, FT-IR and MS spectroscopic methods. To access stability of the investigated caffeine analogues Molecular Dynamic simulations were performed in NAMD 2.9 assuming CHARMM36 force field. To evaluate the antioxidant capacity of new compounds, three different antioxidant assays were used, namely 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH • ) scavenging activity, ferrous ions (Fe 2+ ) chelating activity and Fe 3+ →Fe 2+ reducing ability. In vitro, the ability of new derivatives to protect human erythrocytes against oxidative haemolysis induced by free radical from 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH) was estimated. The cytotoxic activity was tested using MCF-7 breast cancer cells and human erythrocytes. All compounds showed the antioxidant capacity depending mostly on their ferrous ions chelating activity. In the presence of AAPH, some derivatives were able to effectively inhibit the oxidative haemolysis. Two derivatives, namely 8-(methyl(2-(methylamino)ethyl)-amino)caffeine and 8-(methyl(3-(methylamino)propyl)amino)caffeine, showed cytotoxic activity against MCF-7 breast cancer cells but not against human erythrocytes. Therefore, it is concluded that the selected di- and polyamine caffeine analogues, depending on their chemical structure, were able to minimize the oxidative stress and to inhibit the tumour cell grow. The confirmed antioxidant and cytotoxic properties of some caffeine derivatives make them attractive for potential applications in food or pharmaceutical industries.
Investigation of phase transitions of saturated phosphocholine lipid bilayers via molecular dynamics simulations.

PubMed

Khakbaz, Pouyan; Klauda, Jeffery B

2018-08-01

Lipid bilayers play an important role in biological systems as they protect cells against unwanted chemicals and provide a barrier for material inside a cell from leaking out. In this paper, nearly 30 μs of molecular dynamics (MD) simulations were performed to investigate phase transitions of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-phosphocholine (DPPC) lipid bilayers from the liquid crystalline (L α ) to the ripple (P β ) and to the gel phase (L β ). Our MD simulations accurately predict the main transition temperature for the single-component bilayers. A key focus of this work is to quantify the structure of the P β phase for DMPC and compare with measures from x-ray experiments. The P β major arm has similar structure to that of the L β , while the thinner minor arm has interdigitated chains and the transition region between these two regions has large chain splay and disorder. At lower temperatures, our MD simulations predict the formation of the L β phase with tilted fatty acid chains. The P β and L β phases are studied for mixtures of DMPC and DPPC and compare favorably with experiment. Overall, our MD simulations provide evidence for the relevancy of the CHARMM36 lipid force field for structures and add to our understanding of the less-defined P β phase. Copyright © 2018 Elsevier B.V. All rights reserved.
Web interface for Brownian dynamics simulation of ion transport and its applications to beta-barrel pores.

PubMed

Lee, Kyu Il; Jo, Sunhwan; Rui, Huan; Egwolf, Bernhard; Roux, Benoît; Pastor, Richard W; Im, Wonpil

2012-01-30

Brownian dynamics (BD) based on accurate potential of mean force is an efficient and accurate method for simulating ion transport through wide ion channels. Here, a web-based graphical user interface (GUI) is presented for carrying out grand canonical Monte Carlo (GCMC) BD simulations of channel proteins: http://www.charmm-gui.org/input/gcmcbd. The webserver is designed to help users avoid most of the technical difficulties and issues encountered in setting up and simulating complex pore systems. GCMC/BD simulation results for three proteins, the voltage dependent anion channel (VDAC), α-Hemolysin (α-HL), and the protective antigen pore of the anthrax toxin (PA), are presented to illustrate the system setup, input preparation, and typical output (conductance, ion density profile, ion selectivity, and ion asymmetry). Two models for the input diffusion constants for potassium and chloride ions in the pore are compared: scaling of the bulk diffusion constants by 0.5, as deduced from previous all-atom molecular dynamics simulations of VDAC, and a hydrodynamics based model (HD) of diffusion through a tube. The HD model yields excellent agreement with experimental conductances for VDAC and α-HL, while scaling bulk diffusion constants by 0.5 leads to underestimates of 10-20%. For PA, simulated ion conduction values overestimate experimental values by a factor of 1.5-7 (depending on His protonation state and the transmembrane potential), implying that the currently available computational model of this protein requires further structural refinement. Copyright © 2011 Wiley Periodicals, Inc.

Web Interface for Brownian Dynamics Simulation of Ion Transport and Its Applications to Beta-Barrel Pores

PubMed Central

Lee, Kyu Il; Jo, Sunhwan; Rui, Huan; Egwolf, Bernhard; Roux, Benoît; Pastor, Richard W.; Im, Wonpil

2011-01-01

Brownian dynamics (BD) in a suitably constructed potential of mean force is an efficient and accurate method for simulating ion transport through wide ion channels. Here, a web-based graphical user interface (GUI) is presented for grand canonical Monte Carlo (GCMC) BD simulations of channel proteins: http://www.charmm-gui.org/input/gcmcbd. The webserver is designed to help users avoid most of the technical difficulties and issues encountered in setting up and simulating complex pore systems. GCMC/BD simulation results for three proteins, the voltage dependent anion channel (VDAC), α-Hemolysin, and the protective antigen pore of the anthrax toxin (PA), are presented to illustrate system setup, input preparation, and typical output (conductance, ion density profile, ion selectivity, and ion asymmetry). Two models for the input diffusion constants for potassium and chloride ions in the pore are compared: scaling of the bulk diffusion constants by 0.5, as deduced from previous all-atom molecular dynamics simulations of VDAC; and a hydrodynamics based model (HD) of diffusion through a tube. The HD model yields excellent agreement with experimental conductances for VDAC and α-Hemolysin, while scaling bulk diffusion constants by 0.5 leads to underestimates of 10–20%. For PA, simulated ion conduction values overestimate experimental values by a factor of 1.5 to 7 (depending on His protonation state and the transmembrane potential), implying that the currently available computational model of this protein requires further structural refinement. PMID:22102176
An insight to the dynamics of conserved water molecular triad in IMPDH II (human): recognition of cofactor and substrate to catalytic Arg 322.

PubMed

Bairagya, Hridoy R; Mukhopadhyay, Bishnu P; Sekar, K

2009-10-01

Inosine 5' monophosphate dehydrogenase (IMPDH II) is a key enzyme involved in the de novo biosynthesis pathway of purine nucleotides and is also considered to be an excellent target for cancer inhibitor design. The conserve R 322 residue (in human) is thought to play some role in the recognition of inhibitor and cofactor through the catalytic D 364 and N 303. The 15 ns simulation and the water dynamics of the three different PDB structures (1B3O, 1NF7, and 1NFB) of human IMPDH by CHARMM force field have clearly indicated the involvement of three conserved water molecules (W(L), W(M), and W(C)) in the recognition of catalytic residues (R 322, D 364, and N 303) to inhibitor and cofactor. Both the guanidine nitrogen atoms (NH1 and NH 2) of the R 322 have anchored the di- and mono-nucleotide (cofactor and inhibitor) binding domains via the conserved W(C) and W(L) water molecules. Another conserved water molecule WM seems to bridge the two domains including the R 322 and also the W(C) and W(L) through seven centers H-bonding coordination. The conserved water molecular triad (W(C)-W(M)-W(L)) in the protein complex may thought to play some important role in the recognition of inhibitor and cofactor to the protein through R 322 residue.
Connection forces in deformable multibody dynamics

NASA Technical Reports Server (NTRS)

Shabana, A. A.; Chang, C. W.

1989-01-01

In the dynamic formulation of holonomic and nonholonomic systems based on D'Alembert-Lagrange equation, the forces of constraints are maintained in the dynamic equations by introducing auxiliary variables, called Lagrange multipliers. This approach introduces a set of generalized reaction forces associated with the system generalized coordinates. Different sets of variables can be used as generalized coordinates and accordingly, the generalized reactions associated with these generalized coordinates may not be the actual reaction forces at the joints. In rigid body dynamics, the generalized reaction forces and the actual reaction forces at the joints represent equipollent systems of forces since they produce the same total forces and moments at and about any point on the rigid body. This is not, however, the case in deformable body analyses wherein the generalized reaction forces depend on the system generalized reference and elastic coordinates. In this paper, a method for determining the actual reaction forces at the joints from the generalized reaction forces in deformable multibody systems is presented.
pyPcazip: A PCA-based toolkit for compression and analysis of molecular simulation data

NASA Astrophysics Data System (ADS)

Shkurti, Ardita; Goni, Ramon; Andrio, Pau; Breitmoser, Elena; Bethune, Iain; Orozco, Modesto; Laughton, Charles A.

The biomolecular simulation community is currently in need of novel and optimised software tools that can analyse and process, in reasonable timescales, the large generated amounts of molecular simulation data. In light of this, we have developed and present here pyPcazip: a suite of software tools for compression and analysis of molecular dynamics (MD) simulation data. The software is compatible with trajectory file formats generated by most contemporary MD engines such as AMBER, CHARMM, GROMACS and NAMD, and is MPI parallelised to permit the efficient processing of very large datasets. pyPcazip is a Unix based open-source software (BSD licenced) written in Python.
Characterization of Aβ Monomers through the Convergence of Ensemble Properties among Simulations with Multiple Force Fields

DOE PAGES

Rosenman, David J.; Wang, Chunyu; García, Angel E.

2016-01-12

We found that amyloid β (Aβ) monomers represent a base state in the pathways of aggregation that result in the fibrils and oligomers implicated in the pathogenesis of Alzheimer’s disease (AD). The structural properties of these intrinsically disordered peptides remain unclear despite extensive experimental and computational investigations. Further, there are mutations within Aβ that change the way the peptide aggregates and are known to cause familial AD (FAD). Here, we analyze the ensembles of different isoforms (Aβ42 and Aβ40) and mutants (E22Δ, D23N, E22K, E22G, and A2T in Aβ40) of Aβ generated with all-atom replica exchange molecular dynamics (REMD) simulationsmore » on the μs/replica time scale. These were run using three different force field/water model combinations: OPLS-AA/L and TIP3P (“OPLS”), AMBER99sb-ILDN and TIP4P-Ew (“ILDN”), as well as CHARMM22* and TIP3SP (“CHARMM”). Despite fundamental changes in simulation parameters, we find that the resulting ensembles demonstrate a strong convergence in structural properties. In particular, antiparallel contacts between L17–A21 and A30–L34 are prevalent in ensembles of Aβ40, directly forming β sheets in the OPLS and ILDN combinations. A21–A30 commonly forms an interceding region that rarely interacts with the rest of the peptide. Further, Aβ42 contributes new β hairpin motifs involving V40–I41 in both OPLS and ILDN. However, the structural flexibility of the central region and the electrostatic interactions that characterize it are notably different between the different conditions. Further, for OPLS, each of the FAD mutations disrupts central bend character and increases the polymorphism of antiparallel contacts across the central region. However, the studied mutations in the ILDN set primarily encourage more global contacts involving the N-terminus and the central region, and promote the formation of new β topologies that may seed different aggregates involved in disease phenotypes. Furthermore, these differences aside, the large degree of agreement between simulation sets across multiple force fields provides a generalizable characterization of Aβ that is also consistent with experimental data and models.« less
Forces in General Relativity

ERIC Educational Resources Information Center

Ridgely, Charles T.

2010-01-01

Many textbooks dealing with general relativity do not demonstrate the derivation of forces in enough detail. The analyses presented herein demonstrate straightforward methods for computing forces by way of general relativity. Covariant divergence of the stress-energy-momentum tensor is used to derive a general expression of the force experienced…
Analysis of the complex formation, interaction and electron transfer pathway between the "open" conformation of NADPH-cytochrome P450 reductase and aromatase.

PubMed

Dai, Yuejie; Zhen, Jing; Zhang, Xiuli; Zhong, Yonghui; Liu, Shaodan; Sun, Ziyue; Guo, Yue; Wu, Qingli

2015-09-01

The complex structure of human aromatase (CYP19) and the open form of ΔTGEE mutant NADPH-cytochrome P450 reductase (mCPR) was constructed using template-based protein alignment method. Dynamic simulation of formed complex was performed on NAMD 2.9, in which CHARMm all 27_prot_lipid_na force field and an explicit TIP3P water solvent model were applied. The result showed mCPR in its open conformation could steadily combine with aromatase from the proximal face. Data analysis indicates hydrogen bonds and four salt bridges on the binding surface enhance the interaction between the two protein molecules. Amino acid, Lys108 plays a key role in aromatase activity through the formation of a salt bridge with Asp147 and two hydrogen bonds with Asp147 and Gln150 in mCPR. The optimal pathway for the first electron transfer from CPR to aromatase was revealed and calculated using HARLEM software. The rates for solvent mediated and non-solvent mediated electron transfer from FMNH2 to heme were determined as 1.04×10(6)s(-)(1) and 4.86×10(5)s(-)(1) respectively, which indicates the solvent water can facilitate the electron transfer from FMNH2 to heme. This study presents a novel strategy for the study of the protein-protein interactions based on the template-based protein alignment, which may help new aromtase development targeting the electron transfer between mCPR and aromatase. Copyright © 2015 Elsevier Inc. All rights reserved.
Thermodynamic and Structural Properties of Methanol-Water Solutions Using Non-Additive Interaction Models

PubMed Central

Zhong, Yang; Warren, G. Lee; Patel, Sandeep

2014-01-01

We study bulk structural and thermodynamic properties of methanol-water solutions via molecular dynamics simulations using novel interaction potentials based on the charge equilibration (fluctuating charge) formalism to explicitly account for molecular polarization at the atomic level. The study uses the TIP4P-FQ potential for water-water interactions, and the CHARMM-based (Chemistry at HARvard Molecular Mechanics) fluctuating charge potential for methanol-methanol and methanol-water interactions. In terms of bulk solution properties, we discuss liquid densities, enthalpies of mixing, dielectric constants, self-diffusion constants, as well as structural properties related to local hydrogen bonding structure as manifested in radial distribution functions and cluster analysis. We further explore the electronic response of water and methanol in the differing local environments established by the interaction of each species predominantly with molecules of the other species. The current force field for the alcohol-water interaction performs reasonably well for most properties, with the greatest deviation from experiment observed for the excess mixing enthalpies, which are predicted to be too favorable. This is qualitatively consistent with the overestimation of the methanol-water gas-phase interaction energy for the lowest-energy conformer (methanol as proton donor). Hydration free energies for methanol in TIP4P-FQ water are predicted to be −5.6±0.2 kcal/mole, in respectable agreement with the experimental value of −5.1 kcal/mole. With respect to solution micro-structure, the present cluster analysis suggests that the micro-scale environment for concentrations where select thermodynamic quantities reach extremal values is described by a bi-percolating network structure. PMID:18074339
Enhanced Sampling in Free Energy Calculations: Combining SGLD with the Bennett's Acceptance Ratio and Enveloping Distribution Sampling Methods.

PubMed

König, Gerhard; Miller, Benjamin T; Boresch, Stefan; Wu, Xiongwu; Brooks, Bernard R

2012-10-09

One of the key requirements for the accurate calculation of free energy differences is proper sampling of conformational space. Especially in biological applications, molecular dynamics simulations are often confronted with rugged energy surfaces and high energy barriers, leading to insufficient sampling and, in turn, poor convergence of the free energy results. In this work, we address this problem by employing enhanced sampling methods. We explore the possibility of using self-guided Langevin dynamics (SGLD) to speed up the exploration process in free energy simulations. To obtain improved free energy differences from such simulations, it is necessary to account for the effects of the bias due to the guiding forces. We demonstrate how this can be accomplished for the Bennett's acceptance ratio (BAR) and the enveloping distribution sampling (EDS) methods. While BAR is considered among the most efficient methods available for free energy calculations, the EDS method developed by Christ and van Gunsteren is a promising development that reduces the computational costs of free energy calculations by simulating a single reference state. To evaluate the accuracy of both approaches in connection with enhanced sampling, EDS was implemented in CHARMM. For testing, we employ benchmark systems with analytical reference results and the mutation of alanine to serine. We find that SGLD with reweighting can provide accurate results for BAR and EDS where conventional molecular dynamics simulations fail. In addition, we compare the performance of EDS with other free energy methods. We briefly discuss the implications of our results and provide practical guidelines for conducting free energy simulations with SGLD.
Investigation on the individual contributions of N-H...O=C and C-H...O=C interactions to the binding energies of beta-sheet models.

PubMed

Wang, Chang-Sheng; Sun, Chang-Liang

2010-04-15

In this article, the binding energies of 16 antiparallel and parallel beta-sheet models are estimated using the analytic potential energy function we proposed recently and the results are compared with those obtained from MP2, AMBER99, OPLSAA/L, and CHARMM27 calculations. The comparisons indicate that the analytic potential energy function can produce reasonable binding energies for beta-sheet models. Further comparisons suggest that the binding energy of the beta-sheet models might come mainly from dipole-dipole attractive and repulsive interactions and VDW interactions between the two strands. The dipole-dipole attractive and repulsive interactions are further obtained in this article. The total of N-H...H-N and C=O...O=C dipole-dipole repulsive interaction (the secondary electrostatic repulsive interaction) in the small ring of the antiparallel beta-sheet models is estimated to be about 6.0 kcal/mol. The individual N-H...O=C dipole-dipole attractive interaction is predicted to be -6.2 +/- 0.2 kcal/mol in the antiparallel beta-sheet models and -5.2 +/- 0.6 kcal/mol in the parallel beta-sheet models. The individual C(alpha)-H...O=C attractive interaction is -1.2 +/- 0.2 kcal/mol in the antiparallel beta-sheet models and -1.5 +/- 0.2 kcal/mol in the parallel beta-sheet models. These values are important in understanding the interactions at protein-protein interfaces and developing a more accurate force field for peptides and proteins. 2009 Wiley Periodicals, Inc.
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.
Study of the interaction of potassium ion channel protein with micelle by molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Shantappa, Anil; Talukdar, Keka

2018-04-01

Ion channels are proteins forming pore inside the body of all living organisms. This potassium ion channel known as KcsA channel and it is found in the each cell and nervous system. Flow of various ions is regulated by the function of the ion channels. The nerve ion channel protein with protein data bank entry 1BL8, which is basically an ion channel protein in Streptomyces Lividans and which is taken up to form micelle-protein system and the system is analyzed by using molecular dynamics simulation. Firstly, ion channel pore is engineered by CHARMM potential and then Micelle-protein system is subjected to molecular dynamics simulation. For some specific micelle concentration, the protein unfolding is observed.
General purpose force doctrine

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

Weltman, J.J.

In contemporary American strategic parlance, the general purpose forces have come to mean those forces intended for conflict situations other than nuclear war with the Soviet Union. As with all military forces, the general purpose forces are powerfully determined by prevailing conceptions of the problems they must meet and by institutional biases as to the proper way to deal with those problems. This paper deals with the strategic problems these forces are intended to meet, the various and often conflicting doctrines and organizational structures which have been generated in order to meet those problems, and the factors which will influencemore » general purpose doctrine and structure in the future. This paper does not attempt to prescribe technological solutions to the needs of the general purpose forces. Rather, it attempts to display the doctrinal and institutional context within which new technologies must operate, and which will largely determine whether these technologies are accepted into the force structure or not.« less
Electrostatic and induction effects in the solubility of water in alkanes

NASA Astrophysics Data System (ADS)

Asthagiri, D.; Valiya Parambathu, Arjun; Ballal, Deepti; Chapman, Walter G.

2017-08-01

Experiments show that at 298 K and 1 atm pressure, the transfer free energy, μex, of water from its vapor to liquid normal alkanes CnH2n+2 (n =5 …12 ) is negative. Earlier it was found that with the united-atom TraPPE model for alkanes and the SPC/E model for water, one had to artificially enhance the attractive alkane-water cross interaction to capture this behavior. Here we revisit the calculation of μex using the polarizable AMOEBA and the non-polarizable Charmm General (CGenFF) forcefields. We test both the AMOEBA03 and AMOEBA14 water models; the former has been validated with the AMOEBA alkane model while the latter is a revision of AMOEBA03 to better describe liquid water. We calculate μex using the test particle method. With CGenFF, μex is positive and the error relative to experiments is about 1.5 kBT. With AMOEBA, μex is negative and deviations relative to experiments are between 0.25 kBT (AMOEBA14) and 0.5 kBT (AMOEBA03). Quantum chemical calculations in a continuum solvent suggest that zero point effects may account for some of the deviation. Forcefield limitations notwithstanding, electrostatic and induction effects, commonly ignored in consideration of water-alkane interactions, appear to be decisive in the solubility of water in alkanes.
Inspector General, DOD, Oversight of the Air Force Audit Agency Audit of the FY 1999 Air Force General Fund Financial Statements

DTIC Science & Technology

2000-02-14

Consolidated Financial Statements . Our objective was to determine the accuracy and completeness of the Air Force Audit Agency audit of the FY 1999 Air Force General Fund financial statements. See Appendix A for a discussion of the audit
Generalization of Dynamics Learning Across Changes in Movement Amplitude

PubMed Central

Mattar, Andrew A. G.

2010-01-01

Studies on generalization show the nature of how learning is encoded in the brain. Previous studies have shown rather limited generalization of dynamics learning across changes in movement direction, a finding that is consistent with the idea that learning is primarily local. In contrast, studies show a broader pattern of generalization across changes in movement amplitude, suggesting a more general form of learning. To understand this difference, we performed an experiment in which subjects held a robotic manipulandum and made movements to targets along the body midline. Subjects were trained in a velocity-dependent force field while moving to a 15 cm target. After training, subjects were tested for generalization using movements to a 30 cm target. We used force channels in conjunction with movements to the 30 cm target to assess the extent of generalization. Force channels restricted lateral movements and allowed us to measure force production during generalization. We compared actual lateral forces to the forces expected if dynamics learning generalized fully. We found that, during the test for generalization, subjects produced reliably less force than expected. Force production was appropriate for the portion of the transfer movement in which velocities corresponded to those experienced with the 15 cm target. Subjects failed to produce the expected forces when velocities exceeded those experienced in the training task. This suggests that dynamics learning generalizes little beyond the range of one's experience. Consistent with this result, subjects who trained on the 30 cm target showed full generalization to the 15 cm target. We performed two additional experiments that show that interleaved trials to the 30 cm target during training on the 15 cm target can resolve the difference between the current results and those reported previously. PMID:20463200
10 CFR 1047.7 - Use of deadly force.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Use of deadly force. 1047.7 Section 1047.7 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS General Provisions § 1047.7 Use of deadly force. (a) Deadly force means that force which a...
DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosenman, David J.; Wang, Chunyu; García, Angel E.

We found that amyloid β (Aβ) monomers represent a base state in the pathways of aggregation that result in the fibrils and oligomers implicated in the pathogenesis of Alzheimer’s disease (AD). The structural properties of these intrinsically disordered peptides remain unclear despite extensive experimental and computational investigations. Further, there are mutations within Aβ that change the way the peptide aggregates and are known to cause familial AD (FAD). Here, we analyze the ensembles of different isoforms (Aβ42 and Aβ40) and mutants (E22Δ, D23N, E22K, E22G, and A2T in Aβ40) of Aβ generated with all-atom replica exchange molecular dynamics (REMD) simulationsmore » on the μs/replica time scale. These were run using three different force field/water model combinations: OPLS-AA/L and TIP3P (“OPLS”), AMBER99sb-ILDN and TIP4P-Ew (“ILDN”), as well as CHARMM22* and TIP3SP (“CHARMM”). Despite fundamental changes in simulation parameters, we find that the resulting ensembles demonstrate a strong convergence in structural properties. In particular, antiparallel contacts between L17–A21 and A30–L34 are prevalent in ensembles of Aβ40, directly forming β sheets in the OPLS and ILDN combinations. A21–A30 commonly forms an interceding region that rarely interacts with the rest of the peptide. Further, Aβ42 contributes new β hairpin motifs involving V40–I41 in both OPLS and ILDN. However, the structural flexibility of the central region and the electrostatic interactions that characterize it are notably different between the different conditions. Further, for OPLS, each of the FAD mutations disrupts central bend character and increases the polymorphism of antiparallel contacts across the central region. However, the studied mutations in the ILDN set primarily encourage more global contacts involving the N-terminus and the central region, and promote the formation of new β topologies that may seed different aggregates involved in disease phenotypes. Furthermore, these differences aside, the large degree of agreement between simulation sets across multiple force fields provides a generalizable characterization of Aβ that is also consistent with experimental data and models.« less
Discrimination of Native-like States of Membrane Proteins with Implicit Membrane-based Scoring Functions.

PubMed

Dutagaci, Bercem; Wittayanarakul, Kitiyaporn; Mori, Takaharu; Feig, Michael

2017-06-13

A scoring protocol based on implicit membrane-based scoring functions and a new protocol for optimizing the positioning of proteins inside the membrane was evaluated for its capacity to discriminate native-like states from misfolded decoys. A decoy set previously established by the Baker lab (Proteins: Struct., Funct., Genet. 2006, 62, 1010-1025) was used along with a second set that was generated to cover higher resolution models. The Implicit Membrane Model 1 (IMM1), IMM1 model with CHARMM 36 parameters (IMM1-p36), generalized Born with simple switching (GBSW), and heterogeneous dielectric generalized Born versions 2 (HDGBv2) and 3 (HDGBv3) were tested along with the new HDGB van der Waals (HDGBvdW) model that adds implicit van der Waals contributions to the solvation free energy. For comparison, scores were also calculated with the distance-scaled finite ideal-gas reference (DFIRE) scoring function. Z-scores for native state discrimination, energy vs root-mean-square deviation (RMSD) correlations, and the ability to select the most native-like structures as top-scoring decoys were evaluated to assess the performance of the scoring functions. Ranking of the decoys in the Baker set that were relatively far from the native state was challenging and dominated largely by packing interactions that were captured best by DFIRE with less benefit of the implicit membrane-based models. Accounting for the membrane environment was much more important in the second decoy set where especially the HDGB-based scoring functions performed very well in ranking decoys and providing significant correlations between scores and RMSD, which shows promise for improving membrane protein structure prediction and refinement applications. The new membrane structure scoring protocol was implemented in the MEMScore web server ( http://feiglab.org/memscore ).
Free energy determinants of secondary structure formation: III. beta-turns and their role in protein folding.

PubMed

Yang, A S; Hitz, B; Honig, B

1996-06-21

The stability of beta-turns is calculated as a function of sequence and turn type with a Monte Carlo sampling technique. The conformational energy of four internal hydrogen-bonded turn types, I, I', II and II', is obtained by evaluating their gas phase energy with the CHARMM force field and accounting for solvation effects with the Finite Difference Poisson-Boltzmann (FDPB) method. All four turn types are found to be less stable than the coil state, independent of the sequence in the turn. The free-energy penalties associated with turn formation vary between 1.6 kcal/mol and 7.7 kcal/mol, depending on the sequence and turn type. Differences in turn stability arise mainly from intraresidue interactions within the two central residues of the turn. For each combination of the two central residues, except for -Gly-Gly-, the most stable beta-turn type is always found to occur most commonly in native proteins. The fact that a model based on local interactions accounts for the observed preference of specific sequences suggests that long-range tertiary interactions tend to play a secondary role in determining turn conformation. In contrast, for beta-hairpins, long-range interactions appear to dominate. Specifically, due to the right-handed twist of beta-strands, type I' turns for -Gly-Gly- are found to occur with high frequency, even when local energetics would dictate otherwise. The fact that any combination of two residues is found able to adopt a relatively low-energy turn structure explains why the amino acid sequence in turns is highly variable. The calculated free-energy cost of turn formation, when combined with related numbers obtained for alpha-helices and beta-sheets, suggests a model for the initiation of protein folding based on metastable fragments of secondary structure.

ProBiS-CHARMMing: Web Interface for Prediction and Optimization of Ligands in Protein Binding Sites.

PubMed

Konc, Janez; Miller, Benjamin T; Štular, Tanja; Lešnik, Samo; Woodcock, H Lee; Brooks, Bernard R; Janežič, Dušanka

2015-11-23

Proteins often exist only as apo structures (unligated) in the Protein Data Bank, with their corresponding holo structures (with ligands) unavailable. However, apoproteins may not represent the amino-acid residue arrangement upon ligand binding well, which is especially problematic for molecular docking. We developed the ProBiS-CHARMMing web interface by connecting the ProBiS ( http://probis.cmm.ki.si ) and CHARMMing ( http://www.charmming.org ) web servers into one functional unit that enables prediction of protein-ligand complexes and allows for their geometry optimization and interaction energy calculation. The ProBiS web server predicts ligands (small compounds, proteins, nucleic acids, and single-atom ligands) that may bind to a query protein. This is achieved by comparing its surface structure against a nonredundant database of protein structures and finding those that have binding sites similar to that of the query protein. Existing ligands found in the similar binding sites are then transposed to the query according to predictions from ProBiS. The CHARMMing web server enables, among other things, minimization and potential energy calculation for a wide variety of biomolecular systems, and it is used here to optimize the geometry of the predicted protein-ligand complex structures using the CHARMM force field and to calculate their interaction energies with the corresponding query proteins. We show how ProBiS-CHARMMing can be used to predict ligands and their poses for a particular binding site, and minimize the predicted protein-ligand complexes to obtain representations of holoproteins. The ProBiS-CHARMMing web interface is freely available for academic users at http://probis.nih.gov.
Binding, folding and insertion of a β-hairpin peptide at a lipid bilayer surface: Influence of electrostatics and lipid tail packing.

PubMed

Reid, Keon A; Davis, Caitlin M; Dyer, R Brian; Kindt, James T

2018-03-01

Antimicrobial peptides (AMPs) act as host defenses against microbial pathogens. Here we investigate the interactions of SVS-1 (KVKVKVKV d P l PTKVKVKVK), an engineered AMP and anti-cancer β-hairpin peptide, with lipid bilayers using spectroscopic studies and atomistic molecular dynamics simulations. In agreement with literature reports, simulation and experiment show preferential binding of SVS-1 peptides to anionic over neutral bilayers. Fluorescence and circular dichroism studies of a Trp-substituted SVS-1 analogue indicate, however, that it will bind to a zwitterionic DPPC bilayer under high-curvature conditions and folds into a hairpin. In bilayers formed from a 1:1 mixture of DPPC and anionic DPPG lipids, curvature and lipid fluidity are also observed to promote deeper insertion of the fluorescent peptide. Simulations using the CHARMM C36m force field offer complementary insight into timescales and mechanisms of folding and insertion. SVS-1 simulated at an anionic mixed POPC/POPG bilayer folded into a hairpin over a microsecond, the final stage in folding coinciding with the establishment of contact between the peptide's valine sidechains and the lipid tails through a "flip and dip" mechanism. Partial, transient folding and superficial bilayer contact are seen in simulation of the peptide at a zwitterionic POPC bilayer. Only when external surface tension is applied does the peptide establish lasting contact with the POPC bilayer. Our findings reveal the influence of disruption to lipid headgroup packing (via curvature or surface tension) on the pathway of binding and insertion, highlighting the collaborative effort of electrostatic and hydrophobic interactions on interaction of SVS-1 with lipid bilayers. Copyright © 2017 Elsevier B.V. All rights reserved.
A Finite Element Framework for Studying the Mechanical Response of Macromolecules: Application to the Gating of the Mechanosensitive Channel MscL

PubMed Central

Tang, Yuye; Cao, Guoxin; Chen, Xi; Yoo, Jejoong; Yethiraj, Arun; Cui, Qiang

2006-01-01

The gating pathways of mechanosensitive channels of large conductance (MscL) in two bacteria (Mycobacterium tuberculosis and Escherichia coli) are studied using the finite element method. The phenomenological model treats transmembrane helices as elastic rods and the lipid membrane as an elastic sheet of finite thickness; the model is inspired by the crystal structure of MscL. The interactions between various continuum components are derived from molecular-mechanics energy calculations using the CHARMM all-atom force field. Both bacterial MscLs open fully upon in-plane tension in the membrane and the variation of pore diameter with membrane tension is found to be essentially linear. The estimated gating tension is close to the experimental value. The structural variations along the gating pathway are consistent with previous analyses based on structural models with experimental constraints and biased atomistic molecular-dynamics simulations. Upon membrane bending, neither MscL opens substantially, although there is notable and nonmonotonic variation in the pore radius. This emphasizes that the gating behavior of MscL depends critically on the form of the mechanical perturbation and reinforces the idea that the crucial gating parameter is lateral tension in the membrane rather than the curvature of the membrane. Compared to popular all-atom-based techniques such as targeted or steered molecular-dynamics simulations, the finite element method-based continuum-mechanics framework offers a unique alternative to bridge detailed intermolecular interactions and biological processes occurring at large spatial scales and long timescales. It is envisioned that such a hierarchical multiscale framework will find great value in the study of a variety of biological processes involving complex mechanical deformations such as muscle contraction and mechanotransduction. PMID:16731564
Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties

PubMed Central

Martinho, Nuno; Silva, Liana C; Florindo, Helena F; Brocchini, Steve; Zloh, Mire; Barata, Teresa S

2017-01-01

Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behavior and structure–activity relationship has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer-aided molecular design and molecular dynamics simulations to identify optimal topology of a poly(l-glutamic acid) (PG) backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole and Oregon Green 488) and various surface groups (glutamic acid, lysine and tryptophan). Analysis of structural and topological features of all designed dendrimers provided information about their size, shape, internal distribution and dynamic behavior. We have found that four generations of a PG dendrimer are needed to ensure minimal exposure of a core-conjugated fluorophore to external environment and absence of undesired interactions regardless of the surface terminal groups. Our findings suggest that NBD-PG-G4 can provide a suitable scaffold to be used for biophysical studies of surface-modified dendrimers to provide a deeper understanding of their intermolecular interactions, mechanisms of action and trafficking in a biological system. PMID:29026301
Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties.

PubMed

Martinho, Nuno; Silva, Liana C; Florindo, Helena F; Brocchini, Steve; Zloh, Mire; Barata, Teresa S

2017-01-01

Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behavior and structure-activity relationship has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer-aided molecular design and molecular dynamics simulations to identify optimal topology of a poly(l-glutamic acid) (PG) backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole and Oregon Green 488) and various surface groups (glutamic acid, lysine and tryptophan). Analysis of structural and topological features of all designed dendrimers provided information about their size, shape, internal distribution and dynamic behavior. We have found that four generations of a PG dendrimer are needed to ensure minimal exposure of a core-conjugated fluorophore to external environment and absence of undesired interactions regardless of the surface terminal groups. Our findings suggest that NBD-PG-G4 can provide a suitable scaffold to be used for biophysical studies of surface-modified dendrimers to provide a deeper understanding of their intermolecular interactions, mechanisms of action and trafficking in a biological system.
Command Clairvoyance: Strategically Transforming AFRC Through Total Force and Leadership

DTIC Science & Technology

2012-01-19

backstop for 21st century operations. Lieutenant General Charles Stenner , Chief of the Air Force Reserve, encapsulated this by stating, "The Air Force...and it is a venue that requires the Air Force and AFRC to change in unison, as General Stenner acknowledged: The Air Force is under the same...another generation of TFI savvy leaders. Aligned with General Stenner ‟s previous comments, AFRC needs to foster an “adaptive culture” in order to
2. GENERAL VIEW OF SLC3 AIR FORCE BUILDING (BLDG. 761) ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

2. GENERAL VIEW OF SLC-3 AIR FORCE BUILDING (BLDG. 761) FROM THE NORTHWEST - Vandenberg Air Force Base, Space Launch Complex 3, SLC-3 Air Force Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA
1. GENERAL VIEW OF SLC3 AIR FORCE BUILDING (BLDG. 761) ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. GENERAL VIEW OF SLC-3 AIR FORCE BUILDING (BLDG. 761) FROM THE SOUTHWEST - Vandenberg Air Force Base, Space Launch Complex 3, SLC-3 Air Force Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA
Molecular dynamics of β-hairpin models of epigenetic recognition motifs.

PubMed

Zheng, Xiange; Wu, Chuanjie; Ponder, Jay W; Marshall, Garland R

2012-09-26

The conformations and stabilities of the β-hairpin model peptides of Waters (Riemen, A. J.; Waters, M. L. Biochemistry 2009, 48, 1525; Hughes, R. M.; Benshoff, M. L.; Waters, M. L. Chemistry 2007, 13, 5753) have been experimentally characterized as a function of lysine ε-methylation. These models were developed to explore molecular recognition of known epigenetic recognition motifs. This system offered an opportunity to computationally examine the role of cation-π interactions, desolvation of the ε-methylated ammonium groups, and aromatic/aromatic interactions on the observed differences in NMR spectra. AMOEBA, a second-generation force field (Ponder, J. W.; Wu, C.; Ren, P.; Pande, V. S.; Chodera, J. D.; Schnieders, M. J.; Haque, I.; Mobley, D. L.; Lambrecht, D. S.; DiStasio, R. A., Jr.; Head-Gordon, M.; Clark, G. N.; Johnson, M. E.; Head-Gordon, T. J. Phys. Chem. B 2010, 114, 2549), was chosen as it includes both multipole electrostatics and polarizability thought to be essential to accurately characterize such interactions. Independent parametrization of ε-methylated amines was required from which aqueous solvation free energies were estimated and shown to agree with literature values. Molecular dynamics simulations (100 ns) using the derived parameters with model peptides, such as Ac-R-W-V-W-V-N-G-Orn-K(Me)(n)-I-L-Q-NH(2), where n = 0, 1, 2, or 3, were conducted in explicit solvent. Distances between the centers of the indole rings of the two-tryptophan residues, 2 and 4, and the ε-methylated ammonium group on Lys-9 as well as the distance between the N- and C-termini were monitored to estimate the strength and orientation of the cation-π and aromatic/aromatic interactions. In agreement with the experimental data, the stability of the β-hairpin increased significantly with lysine ε-methylation. The ability of MD simulations to reproduce the observed NOEs for the four peptides was further estimated for the monopole-based force fields, AMBER, CHARMM, and OPLSAA. AMOEBA correctly predicted over 80% of the observed NOEs for all 4 peptides, while the three-monopole force fields were 40-50% predictive in only 2 cases and approximately 10% in the other 10 examples. Preliminary analysis suggests that the decreased cost of desolvation of the substituted ammonium group significantly compensated for the reduced cation-π interaction resulting from the increased separation due to steric bulk of the ε-methylated amines.
The United States Air Force Reserve Officer Training Corps: Looking to the Future

DTIC Science & Technology

1991-03-04

Brigadier General Robin G. Tornow Commandant, Air Force ROTC (Note 25) Over the years, Air Force ROTC has developed many strong points. Paramount among...maintaining a leaner and more capable force for the future. Brigadier General Robin G. Tornow Commandant, Air Force ROTC (Note 35) This alternative
From 35,000 FT: Getting Air Force Squadron Commanders to Altitude Amid a Resource Constrained Environment

DTIC Science & Technology

Force Inspection System, the Inspector General Complaints Resolution Program, and the Total Force Climate Survey, this paper sought to understand what...by means of the Air Force Inspection System. This research determined that the data collected by the Inspector General and the Total Force Climate
Some fundamentals regarding kinematics and generalized forces for multibody dynamics

NASA Technical Reports Server (NTRS)

Hodges, Dewey H.

1990-01-01

In order to illustrate the various forms in which generalized forces can arise from diverse subsystem analyses in multibody dynamics, intrinsic dynamical equations for the rotational dynamics of a rigid body are derived from Hamilton's principle. Two types of generalized forces are derived: (1) those associated with the virtual rotation vector in some orthogonal basis, and (2) those associated with varying generalized coordinates. As one physical or kinematical result (such as a frequency or a specific direction cosine) cannot rely on this selection, a 'blind' coupling of two models in which generalized forces are calculated in different ways would be wrong. Both types should use the same rotational coordinates and should denote the virtual rotation on a similar basis according to method 1, or in terms of common rotational coordinates and their diversifications as in method 2. Alternatively, the generalized forces and coordinates of one model may be transformed to those of the other.
10 CFR 1047.6 - Use of physical force when making an arrest.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Use of physical force when making an arrest. 1047.6 Section 1047.6 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS General Provisions § 1047.6 Use of physical force when making an arrest...
DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalligiannaki, Evangelia, E-mail: ekalligian@tem.uoc.gr; Harmandaris, Vagelis, E-mail: harman@uoc.gr; Institute of Applied and Computational Mathematics

Using the probabilistic language of conditional expectations, we reformulate the force matching method for coarse-graining of molecular systems as a projection onto spaces of coarse observables. A practical outcome of this probabilistic description is the link of the force matching method with thermodynamic integration. This connection provides a way to systematically construct a local mean force and to optimally approximate the potential of mean force through force matching. We introduce a generalized force matching condition for the local mean force in the sense that allows the approximation of the potential of mean force under both linear and non-linear coarse grainingmore » mappings (e.g., reaction coordinates, end-to-end length of chains). Furthermore, we study the equivalence of force matching with relative entropy minimization which we derive for general non-linear coarse graining maps. We present in detail the generalized force matching condition through applications to specific examples in molecular systems.« less
Microtunneling systems and methods of use

DOEpatents

Richardson, John G.; Kostelnik, Kevin M.; Nickelson, Reva A.; Sloan, Paul A.

2006-07-04

A tunneling system including a tunneling apparatus including a cutting structure for forming a borehole and at least one linkage section for transmitting a force generally toward the cutting structure is disclosed. A method of disposing a casing string within a subterranean formation by applying a force generally to the trailing end of the tunneling apparatus, generally toward the leading end thereof, but without transmitting the entire force through the entire casing string is also disclosed. At least one linkage section extending within but not in contact with at least one casing section of the casing string may transmit the force. Also, a force limiting member may limit a force applied to the casing string.
Building Coalitions for Humanitarian Operations -- Operation Provide Comfort

DTIC Science & Technology

1992-04-15

When notified of his new appointment, General Shalilkashvili was the Deputy Commander of United States Army Europe (USAREUR). He arrived at the...refugees. EUCOM selected Air Force Major General James L. Jamerson as the commander of JTF-PC. General Jamerson was serving as the Deputy Commander of U.S...located with JTF-PC headquarters. AFFOR was under the command of Air Force Brigadier General James L. Hobson, Jr. The SOF forces were under the
Design, synthesis and antimalarial screening of some hybrid 4-aminoquinoline-triazine derivatives against pf-DHFR-TS.

PubMed

Sahu, Supriya; Ghosh, Surajit Kumar; Kalita, Junmoni; Dutta, Mayurakhi; Bhat, Hans Raj

2016-04-01

Existing antifolate antimalarial drugs have shown resistance due to the mutations at some amino acid positions of Plasmodium falciparum DHFR-TS. In the present study, to overcome this resistance, a new series of hybrid 4-aminoquinoline-triazine derivatives were designed and docked into the active site of Pf-DHFR-TS (PDB i.d. 1J3K) using validated CDOCKER protocol. Binding energy was calculated by applying CHARMm forcefield. Binding energy and the pattern of interaction of the docked compounds were analysed. Fifteen compounds were selected for synthesis based on their binding energy values and docking poses. Synthesized compounds were characterised by FTIR, (1)H NMR, (13)C NMR, mass spectroscopy and were screened for antimalarial activity against 3D7 strain of Plasmodium falciparum. Copyright © 2016 Elsevier Inc. All rights reserved.
Atom Tunneling in the Hydroxylation Process of Taurine/α-Ketoglutarate Dioxygenase Identified by Quantum Mechanics/Molecular Mechanics Simulations.

PubMed

Álvarez-Barcia, Sonia; Kästner, Johannes

2017-06-01

Taurine/α-ketoglutarate dioxygenase is one of the most studied α-ketoglutarate-dependent dioxygenases (αKGDs), involved in several biotechnological applications. We investigated the key step in the catalytic cycle of the αKGDs, the hydrogen transfer process, by a quantum mechanics/molecular mechanics approach (B3LYP/CHARMM22). Analysis of the charge and spin densities during the reaction demonstrates that a concerted mechanism takes place, where the H atom transfer happens simultaneously with the electron transfer from taurine to the Fe═O cofactor. We found the quantum tunneling of the hydrogen atom to increase the rate constant by a factor of 40 at 5 °C. As a consequence, a quite high kinetic isotope effect close to 60 is obtained, which is consistent with the experimental value.
Computational study of a calcium release-activated calcium channel

NASA Astrophysics Data System (ADS)

Talukdar, Keka; Shantappa, Anil

2016-05-01

The naturally occurring proteins that form hole in membrane are commonly known as ion channels. They play multiple roles in many important biological processes. Deletion or alteration of these channels often leads to serious problems in the physiological processes as it controls the flow of ions through it. The proper maintenance of the flow of ions, in turn, is required for normal health. Here we have investigated the behavior of a calcium release-activated calcium ion channel with pdb entry 4HKR in Drosophila Melanogaster. The equilibrium energy as well as molecular dynamics simulation is performed first. The protein is subjected to molecular dynamics simulation to find their energy minimized value. Simulation of the protein in the environment of water and ions has given us important results too. The solvation energy is also found using Charmm potential.
10 CFR 1047.5 - Exercise of arrest authority-general guidelines.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false Exercise of arrest authority-general guidelines. 1047.5 Section 1047.5 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS General Provisions § 1047.5 Exercise of arrest authority—general...

10 CFR 1047.5 - Exercise of arrest authority-general guidelines.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 4 2014-01-01 2014-01-01 false Exercise of arrest authority-general guidelines. 1047.5 Section 1047.5 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS General Provisions § 1047.5 Exercise of arrest authority—general...
10 CFR 1047.5 - Exercise of arrest authority-general guidelines.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 4 2013-01-01 2013-01-01 false Exercise of arrest authority-general guidelines. 1047.5 Section 1047.5 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS General Provisions § 1047.5 Exercise of arrest authority—general...
10 CFR 1047.5 - Exercise of arrest authority-general guidelines.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 4 2012-01-01 2012-01-01 false Exercise of arrest authority-general guidelines. 1047.5 Section 1047.5 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS General Provisions § 1047.5 Exercise of arrest authority—general...
10 CFR 1047.5 - Exercise of arrest authority-general guidelines.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Exercise of arrest authority-general guidelines. 1047.5 Section 1047.5 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS General Provisions § 1047.5 Exercise of arrest authority—general...
Operational Leadership in Kosovo

DTIC Science & Technology

2004-02-09

ARRC) LGEN Michael Jackson Allied Air Forces North (COMAIRNORTH) GEN John Jumper Allied Naval Forces North (COMNAVNORTH) U.K. Allied Naval Forces South... Michael Jackson reportedly told the US commander (Clark) during one heated exchange. When General Jackson refused, General Clark asked Admiral James
Task Force on the Role of General Education in Associate Science Degree Programs. Final Report and Recommendations.

ERIC Educational Resources Information Center

Weyers, Lori; Langerman, Philip

In 1989-90, the General Education Task Force of the Wisconsin Technical College System (WTCS) was convened to determine the role of the general education curriculum in the attainment of skills that enhance the likelihood of success among technical college graduates in their careers, homes and communities. The Task Force consisted of at least one…
78 FR 63452 - Meeting of the National Commission on the Structure of the Air Force; Correction to Meetings of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-24

... witnesses scheduled to testify. October 24, 2013 Agenda from 8:00 a.m. to 12:00 p.m.: Major General Brian... General John Posner, Director of Global Power Programs in the Office of the Assistant Secretary of the Air Force, Acquisition, Headquarters U.S. Air Force, Washington DC; and Major General Mark Bartman...
The Challenge and the Promise: Strengthening the Force, Preventing Suicide and Saving Lives. Final Report of the Department of Defense Task Force on the Prevention of Suicide by Members of the Armed Forces

DTIC Science & Technology

2010-08-01

Sergeant Major Ronald Green USMC Major General Philip Volpe, DO, MC USA Marjan Ghahramounlou Holloway, PhD Commander Aaron...and one civilian member serving as co-chairs for the group. Major General Philip Volpe, initially the Deputy Commander of Joint Task Force, National...and representation from each Service. Major General Philip Volpe was appointed as the military co-chair, and Ms. Bonnie Carroll was elected as the
The Oklahoma Attorney General's Task Force report on the State of End-of-Life Health Care, 2005.

PubMed

Edmondson, W A Drew

2005-05-01

This article includes the recommendations submitted by the 15 members of the Oklahoma Attorney General's Task Force in their Report on the State of End-of-Life Health Care. The task force was created on April 21, 2004, and their report was accepted by Attorney General W.A. Drew Edmondson at a press conference April 11, 2005. It has been forwarded to members of the Oklahoma Legislature, relevant state agencies and organizations with an invitation to join with members of the task force to continue efforts to improve end-of-life care for Oklahomans. Copies of the report are available upon request to the Office of Attorney General.
Diffusion and spectroscopy of water and lipids in fully hydrated dimyristoylphosphatidylcholine bilayer membranes

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

Yang, J.; Martí, J., E-mail: jordi.marti@upc.edu; Calero, C.

2014-03-14

Microscopic structure and dynamics of water and lipids in a fully hydrated dimyristoylphosphatidylcholine phospholipid lipid bilayer membrane in the liquid-crystalline phase have been analyzed with all-atom molecular dynamics simulations based on the recently parameterized CHARMM36 force field. The diffusive dynamics of the membrane lipids and of its hydration water, their reorientational motions as well as their corresponding spectral densities, related to the absorption of radiation, have been considered for the first time using the present force field. In addition, structural properties such as density and pressure profiles, a deuterium-order parameter, surface tension, and the extent of water penetration in themore » membrane have been analyzed. Molecular self-diffusion, reorientational motions, and spectral densities of atomic species reveal a variety of time scales playing a role in membrane dynamics. The mechanisms of lipid motion strongly depend on the time scale considered, from fast ballistic translation at the scale of picoseconds (effective diffusion coefficients of the order of 10{sup −5} cm{sup 2}/s) to diffusive flow of a few lipids forming nanodomains at the scale of hundreds of nanoseconds (diffusion coefficients of the order of 10{sup −8} cm{sup 2}/s). In the intermediate regime of sub-diffusion, collisions with nearest neighbors prevent the lipids to achieve full diffusion. Lipid reorientations along selected directions agree well with reported nuclear magnetic resonance data and indicate two different time scales, one about 1 ns and a second one in the range of 2–8 ns. We associated the two time scales of reorientational motions with angular distributions of selected vectors. Calculated spectral densities corresponding to lipid and water reveal an overall good qualitative agreement with Fourier transform infrared spectroscopy experiments. Our simulations indicate a blue-shift of the low frequency spectral bands of hydration water as a result of its interaction with lipids. We have thoroughly analyzed the physical meaning of all spectral features from lipid atomic sites and correlated them with experimental data. Our findings include a “wagging of the tails” frequency around 30 cm{sup −1}, which essentially corresponds to motions of the tail-group along the instantaneous plane formed by the two lipid tails, i.e., in-plane oscillations are clearly of bigger importance than those along the normal-to-the plane direction.« less
[Analysis of Conformational Features of Watson-Crick Duplex Fragments by Molecular Mechanics and Quantum Mechanics Methods].

PubMed

Poltev, V I; Anisimov, V M; Sanchez, C; Deriabina, A; Gonzalez, E; Garcia, D; Rivas, F; Polteva, N A

2016-01-01

It is generally accepted that the important characteristic features of the Watson-Crick duplex originate from the molecular structure of its subunits. However, it still remains to elucidate what properties of each subunit are responsible for the significant characteristic features of the DNA structure. The computations of desoxydinucleoside monophosphates complexes with Na-ions using density functional theory revealed a pivotal role of DNA conformational properties of single-chain minimal fragments in the development of unique features of the Watson-Crick duplex. We found that directionality of the sugar-phosphate backbone and the preferable ranges of its torsion angles, combined with the difference between purines and pyrimidines. in ring bases, define the dependence of three-dimensional structure of the Watson-Crick duplex on nucleotide base sequence. In this work, we extended these density functional theory computations to the minimal' fragments of DNA duplex, complementary desoxydinucleoside monophosphates complexes with Na-ions. Using several computational methods and various functionals, we performed a search for energy minima of BI-conformation for complementary desoxydinucleoside monophosphates complexes with different nucleoside sequences. Two sequences are optimized using ab initio method at the MP2/6-31++G** level of theory. The analysis of torsion angles, sugar ring puckering and mutual base positions of optimized structures demonstrates that the conformational characteristic features of complementary desoxydinucleoside monophosphates complexes with Na-ions remain within BI ranges and become closer to the corresponding characteristic features of the Watson-Crick duplex crystals. Qualitatively, the main characteristic features of each studied complementary desoxydinucleoside monophosphates complex remain invariant when different computational methods are used, although the quantitative values of some conformational parameters could vary lying within the limits typical for the corresponding family. We observe that popular functionals in density functional theory calculations lead to the overestimated distances between base pairs, while MP2 computations and the newer complex functionals produce the structures that have too close atom-atom contacts. A detailed study of some complementary desoxydinucleoside monophosphate complexes with Na-ions highlights the existence of several energy minima corresponding to BI-conformations, in other words, the complexity of the relief pattern of the potential energy surface of complementary desoxydinucleoside monophosphate complexes. This accounts for variability of conformational parameters of duplex fragments with the same base sequence. Popular molecular mechanics force fields AMBER and CHARMM reproduce most of the conformational characteristics of desoxydinucleoside monophosphates and their complementary complexes with Na-ions but fail to reproduce some details of the dependence of the Watson-Crick duplex conformation on the nucleotide sequence.
A Study of Some Issues Which May Influence the Question of a Role for Free-Fall Weapons.

DTIC Science & Technology

1981-06-01

Environment Precision-Guided Munitions The Middle East American Public Ophinion General Target Categories The Horn of Africa Force Application Environ- and...DISCUSSION ........... ....................... 5 I. THE GENERAL MILIEU OF FORCE APPLICATION IN THE 198OS ........ ii A. Some Aspects of the...Force Application Environment of the 1980s ......... .. 32 IV. GENERAL TARGET CATEGORIES AND DELIVERY SYSTEMS ............ ... 38 A. Air Supremacy
Modularity: An Application of General Systems Theory to Military Force Development

DTIC Science & Technology

2005-01-01

1999). Context, modularity, and the cultural constitution of development. In P. Lloyd & C. Fernyhough (Eds.), Lev Vygotsky : Critical assessments...of General Systems Theory to Military Force Development 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...Prescribed by ANSI Std Z39-18 MODULARITY: AN APPLICATION OF GENERAL SYSTEMS THEORY TO MILITARY FORCE DEVELOPMENT 279 R SEARCH MODULARITY: AN APPLICATION OF
A method of assigning socio-economic status classification to British Armed Forces personnel.

PubMed

Yoong, S Y; Miles, D; McKinney, P A; Smith, I J; Spencer, N J

1999-10-01

The objective of this paper was to develop and evaluate a socio-economic status classification method for British Armed Forces personnel. Two study groups comprising of civilian and Armed Forces families were identified from livebirths delivered between 1 January-30 June 1996 within the Northallerton Health district which includes Catterick Garrison and RAF Leeming. The participants were the parents of babies delivered at a District General Hospital, comprising of 436 civilian and 162 Armed Forces families. A new classification method was successfully used to assign Registrar General's social classification to Armed Forces personnel. Comparison of the two study groups showed a significant difference in social class distribution (p = 0.0001). This study has devised a new method for classifying occupations within the Armed Forces to categories of social class thus permitting comparison with Registrar General's classification.
Lightweight Object Oriented Structure analysis: Tools for building Tools to Analyze Molecular Dynamics Simulations

PubMed Central

Romo, Tod D.; Leioatts, Nicholas; Grossfield, Alan

2014-01-01

LOOS (Lightweight Object-Oriented Structure-analysis) is a C++ library designed to facilitate making novel tools for analyzing molecular dynamics simulations by abstracting out the repetitive tasks, allowing developers to focus on the scientifically relevant part of the problem. LOOS supports input using the native file formats of most common biomolecular simulation packages, including CHARMM, NAMD, Amber, Tinker, and Gromacs. A dynamic atom selection language based on the C expression syntax is included and is easily accessible to the tool-writer. In addition, LOOS is bundled with over 120 pre-built tools, including suites of tools for analyzing simulation convergence, 3D histograms, and elastic network models. Through modern C++ design, LOOS is both simple to develop with (requiring knowledge of only 4 core classes and a few utility functions) and is easily extensible. A python interface to the core classes is also provided, further facilitating tool development. PMID:25327784
Lightweight object oriented structure analysis: tools for building tools to analyze molecular dynamics simulations.

PubMed

Romo, Tod D; Leioatts, Nicholas; Grossfield, Alan

2014-12-15

LOOS (Lightweight Object Oriented Structure-analysis) is a C++ library designed to facilitate making novel tools for analyzing molecular dynamics simulations by abstracting out the repetitive tasks, allowing developers to focus on the scientifically relevant part of the problem. LOOS supports input using the native file formats of most common biomolecular simulation packages, including CHARMM, NAMD, Amber, Tinker, and Gromacs. A dynamic atom selection language based on the C expression syntax is included and is easily accessible to the tool-writer. In addition, LOOS is bundled with over 140 prebuilt tools, including suites of tools for analyzing simulation convergence, three-dimensional histograms, and elastic network models. Through modern C++ design, LOOS is both simple to develop with (requiring knowledge of only four core classes and a few utility functions) and is easily extensible. A python interface to the core classes is also provided, further facilitating tool development. © 2014 Wiley Periodicals, Inc.
Comparison of Theodorsen's Unsteady Aerodynamic Forces with Doublet Lattice Generalized Aerodynamic Forces

NASA Technical Reports Server (NTRS)

Perry, Boyd, III

2017-01-01

This paper identifies the unsteady aerodynamic forces and moments for a typical section contained in the NACA Report No. 496, "General Theory of Aerodynamic Instability and the Mechanism of Flutter," by Theodore Theodorsen. These quantities are named Theodorsen's aerodynamic forces (TAFs). The TAFs are compared to the generalized aerodynamic forces (GAFs) for a very high aspect ratio wing (AR = 20) at zero Mach number computed by the doublet lattice method. Agreement between TAFs and GAFs is very-good-to-excellent. The paper also reveals that simple proportionality relationships that are known to exist between the real parts of some GAFs and the imaginary parts of others also hold for the real and imaginary parts of the corresponding TAFs.
Incomplete Victory: General Allenby and Mission Command in Palestine, 1917-1918

DTIC Science & Technology

2012-12-14

challenges in mission command. While General Allenby, commanding the Allied Egyptian Expeditionary Force (EEF), gained several victories in the...challenges in mission command. While General Allenby, commanding the Allied Egyptian Expeditionary Force (EEF), gained several victories in the early stages...
Lyapunov stability analysis for the generalized Kapitza pendulum

NASA Astrophysics Data System (ADS)

Druzhinina, O. V.; Sevastianov, L. A.; Vasilyev, S. A.; Vasilyeva, D. G.

2017-12-01

In this work generalization of Kapitza pendulum whose suspension point moves in the vertical and horizontal planes is made. Lyapunov stability analysis of the motion for this pendulum subjected to excitation of periodic driving forces and stochastic driving forces that act in the vertical and horizontal planes has been studied. The numerical study of the random motion for generalized Kapitza pendulum under stochastic driving forces has made. It is shown the existence of stable quasi-periodic motion for this pendulum.
DoD Task Force on the Prevention of the Suicide by Members of the Armed Forces

DTIC Science & Technology

2010-08-01

Ronald Green USMC Major General Philip Volpe, DO, MC USA Marjan Ghahramounlou Holloway, PhD Commander Aaron Werbel, PhD USN Table of Contents...and one civilian member serving as co-chairs for the group. Major General Philip Volpe, initially the Deputy Commander of Joint Task Force, National...and representation from each Service. Major General Philip Volpe was appointed as the military co-chair, and Ms. Bonnie Carroll was elected as the

Adaptive enhanced sampling by force-biasing using neural networks

NASA Astrophysics Data System (ADS)

Guo, Ashley Z.; Sevgen, Emre; Sidky, Hythem; Whitmer, Jonathan K.; Hubbell, Jeffrey A.; de Pablo, Juan J.

2018-04-01

A machine learning assisted method is presented for molecular simulation of systems with rugged free energy landscapes. The method is general and can be combined with other advanced sampling techniques. In the particular implementation proposed here, it is illustrated in the context of an adaptive biasing force approach where, rather than relying on discrete force estimates, one can resort to a self-regularizing artificial neural network to generate continuous, estimated generalized forces. By doing so, the proposed approach addresses several shortcomings common to adaptive biasing force and other algorithms. Specifically, the neural network enables (1) smooth estimates of generalized forces in sparsely sampled regions, (2) force estimates in previously unexplored regions, and (3) continuous force estimates with which to bias the simulation, as opposed to biases generated at specific points of a discrete grid. The usefulness of the method is illustrated with three different examples, chosen to highlight the wide range of applicability of the underlying concepts. In all three cases, the new method is found to enhance considerably the underlying traditional adaptive biasing force approach. The method is also found to provide improvements over previous implementations of neural network assisted algorithms.
Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations

PubMed Central

DeMarco, Kevin R.; Bekker, Slava; Clancy, Colleen E.; Noskov, Sergei Y.; Vorobyov, Igor

2018-01-01

Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel Kv11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety pharmacology, and identifies some of the challenges that lie therein. PMID:29449809
Differential Deformability of the DNA Minor Groove and Altered BI/BII Backbone Conformational Equilibrium by the Monovalent Ions Li+, Na+, K+ and Rb+ via Water-Mediated Hydrogen Bonding

PubMed Central

Savelyev, Alexey; MacKerell, Alexander D.

2015-01-01

Recently, we reported the differential impact of the monovalent cations Li+, Na+, K+ and Rb+ on DNA conformational properties. These were identified from variations in the calculated solution-state X-ray DNA spectra as a function of the ion type in the solvation buffer in MD simulations using our recently developed polarizable force field based on the classical Drude oscillator. Changes in the DNA structure were found to mainly involve variations in the minor groove width. Because minor groove dimensions vary significantly in protein-DNA complexes and have been shown to play a critical role in both specific and nonspecific DNA readout, understanding the origins of the observed differential DNA modulation by the first-group monovalent ions is of great biological importance. In the present study we show that the primary microscopic mechanism for the phenomenon is the formation of the water-mediated hydrogen bonds between solvated cations located inside the minor groove and simultaneously to two DNA strands, a process whose intensity and impact on DNA structure depends on both the type of the ion and DNA sequence. Additionally, it is shown that formation of such ion-DNA hydrogen bond complexes appreciably modulates the conformation of the backbone by increasing the population of the BII substate. Notably, the differential impact of the ions on DNA conformational behavior is only predicted by the Drude polarizable model for DNA, with virtually no effect observed from MD simulations utilizing the additive CHARMM36 model. Analysis of dipole moments of the water shows the Drude SWM4 model to possess high sensitivity to changes in the local environment, which indicates the important role of electronic polarization in the salt-dependent conformational properties. This also suggests that inclusion of polarization effects is required to model even relatively simple biological systems such as DNA in various ionic solutions. PMID:26575937
Collision-Induced Dissociation of Electrosprayed Protein Complexes: An All-Atom Molecular Dynamics Model with Mobile Protons.

PubMed

Popa, Vlad; Trecroce, Danielle A; McAllister, Robert G; Konermann, Lars

2016-06-16

Electrospray ionization mass spectrometry (ESI-MS) has become an indispensable technique for examining noncovalent protein complexes. Collision-induced dissociation (CID) of these multiply protonated gaseous ions usually culminates in ejection of a single subunit with a disproportionately large amount of charge. Experiments suggest that this process involves subunit unfolding prior to separation from the residual complex, as well as H(+) migration onto the unravelling chain. Molecular dynamics (MD) simulations are a promising avenue for gaining detailed insights into these CID events. Unfortunately, typical MD algorithms do not allow for mobile protons. Here we address this limitation by implementing a strategy that combines atomistic force fields (such as OPLS/AA and CHARMM36) with a proton hopping algorithm, focusing on the tetrameric complexes transthyretin and streptavidin. Protons are redistributed over all acidic and basic sites in 20 ps intervals, subject to an energy function that reflects electrostatic interactions and proton affinities. Our simulations predict that nativelike conformers at the onset of collisional heating contain multiple salt bridges. Collisional heating initially causes subtle structural changes that lead to a gradual decline of these zwitterionic patterns. Many of the MD runs show gradual unfolding of a single subunit in conjunction with H(+) migration, culminating in subunit separation from the complex. However, there are also instances where two or more chains start to unfold simultaneously, giving rise to charge competition. The scission point where the "winning" subunit separates from the complex can be attained for different degrees of unfolding, giving rise to product ions in various charge states. The simulated product ion distributions are in close agreement with experimental CID data. Proton enrichment in the departing subunit is driven by charge-charge repulsion, but the combination of salt bridge depletion, charge migration, and proton affinity causes surprising compensation effects among the various energy terms. It appears that this work provides the most detailed account to date of the mechanism whereby noncovalent protein complexes disassemble during CID.
Multibody correlations in the hydrophobic solvation of glycine peptides

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

Harris, Robert C.; Drake, Justin A.; Pettitt, B. Montgomery, E-mail: mpettitt@utmb.edu

2014-12-14

Protein collapse during folding is often assumed to be driven by a hydrophobic solvation energy (ΔG{sub vdw}) that scales linearly with solvent-accessible surface area (A). In a previous study, we argued that ΔG{sub vdw}, as well as its attractive (ΔG{sub att}) and repulsive (ΔG{sub rep}) components, was not simply a linear function of A. We found that the surface tensions, γ{sub rep}, γ{sub att}, and γ{sub vdw}, gotten from ΔG{sub rep}, ΔG{sub att}, and ΔG{sub vdw} against A for four configurations of deca-alanine differed from those obtained for a set of alkanes. In the present study, we extend our analysismore » to fifty decaglycine structures and atomic decompositions. We find that different configurations of decaglycine generate different estimates of γ{sub rep}. Additionally, we considered the reconstruction of the solvation free energy from scaling the free energy of solvation of each atom type, free in solution. The free energy of the isolated atoms, scaled by the inverse surface area the atom would expose in the molecule does not reproduce the γ{sub rep} for the intact decaglycines. Finally, γ{sub att} for the decaglycine conformations is much larger in magnitude than those for deca-alanine or the alkanes, leading to large negative values of γ{sub vdw} (−74 and −56 cal/mol/Å{sup 2} for CHARMM27 and AMBER ff12sb force fields, respectively). These findings imply that ΔG{sub vdw} favors extended rather than compact structures for decaglycine. We find that ΔG{sub rep} and ΔG{sub vdw} have complicated dependencies on multibody correlations between solute atoms, on the geometry of the molecular surface, and on the chemical identities of the atoms.« less
Integration of a sensor based multiple robot environment for space applications: The Johnson Space Center Teleoperator Branch Robotics Laboratory

NASA Technical Reports Server (NTRS)

Hwang, James; Campbell, Perry; Ross, Mike; Price, Charles R.; Barron, Don

1989-01-01

An integrated operating environment was designed to incorporate three general purpose robots, sensors, and end effectors, including Force/Torque Sensors, Tactile Array sensors, Tactile force sensors, and Force-sensing grippers. The design and implementation of: (1) the teleoperation of a general purpose PUMA robot; (2) an integrated sensor hardware/software system; (3) the force-sensing gripper control; (4) the host computer system for dual Robotic Research arms; and (5) the Ethernet integration are described.
Uncertainties in Carbon Dioxide Radiative Forcing in Atmospheric General Circulation Models

NASA Technical Reports Server (NTRS)

Cess, R. D.; Zhang, M.-H.; Potter, G. L.; Gates, W. L.; Taylor, K. E.; Barker, H. W.; Colman, R. A.; Fraser, J. R.; McAvaney, B. J.; Dazlich, D. A.;

1993-01-01

Global warming, caused by an increase in the concentrations of greenhouse gases, is the direct result of greenhouse gas-induced radiative forcing. When a doubling of atmospheric carbon dioxide is considered, this forcing differed substantially among 15 atmospheric general circulation models. Although there are several potential causes, the largest contributor was the carbon dioxide radiation parameterizations of the models.

Force Control and Its Relation to Timing. Cognitive Science Program, Technical Report No. 86-4.

ERIC Educational Resources Information Center

Keele, Steven W.; And Others

Timing and speed are suggested to be the two general factors of coordination that differentiate people across a variety of motor movements. This study provides evidence for a third general factor of coordination, that of force control. Subjects that exhibit low variability in reproducing a target force with one effector, such as the finger, show…
10 CFR 1049.5 - Exercise of arrest authority-General guidelines.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 4 2013-01-01 2013-01-01 false Exercise of arrest authority-General guidelines. 1049.5 Section 1049.5 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS OF THE STRATEGIC PETROLEUM RESERVE § 1049.5 Exercise of arrest authority...
10 CFR 1049.5 - Exercise of arrest authority-General guidelines.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false Exercise of arrest authority-General guidelines. 1049.5 Section 1049.5 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS OF THE STRATEGIC PETROLEUM RESERVE § 1049.5 Exercise of arrest authority...
10 CFR 1049.5 - Exercise of arrest authority-General guidelines.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 4 2014-01-01 2014-01-01 false Exercise of arrest authority-General guidelines. 1049.5 Section 1049.5 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS OF THE STRATEGIC PETROLEUM RESERVE § 1049.5 Exercise of arrest authority...
10 CFR 1049.5 - Exercise of arrest authority-General guidelines.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 4 2012-01-01 2012-01-01 false Exercise of arrest authority-General guidelines. 1049.5 Section 1049.5 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS OF THE STRATEGIC PETROLEUM RESERVE § 1049.5 Exercise of arrest authority...
10 CFR 1049.5 - Exercise of arrest authority-General guidelines.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Exercise of arrest authority-General guidelines. 1049.5 Section 1049.5 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS OF THE STRATEGIC PETROLEUM RESERVE § 1049.5 Exercise of arrest authority...
Generalized formulation of the interactions between soft spheres

NASA Astrophysics Data System (ADS)

Alonso-Marroquín, F.; McNamara, S.

2014-10-01

The goal of this paper is to identify the most general formulation that consistently links the different degrees of freedom in a contact between spherical soft particles. These contact laws have two parts: a set of "generalized contact velocities" that characterize the relative motion of the two particles, and a set of "generalized contact forces" that characterize the interparticle forces. One well known constraint on contact models is that the contact velocities must be objective. This requirement fixes the number of linearly independent contact velocities. We also present a previously unnoticed (in this context) constraint, namely, that the velocities and forces must be related in such a way that the stiffness matrix is symmetric. This constraint also places restrictions on the coupling between the contact forces. Within our generalized contact model, we discuss the expression for rolling velocity that need to be used in the calculation of rolling resistance, and the risk or producing perpetual mobile when other expressions of rolling velocity are using instead.
Forces between a rigid probe particle and a liquid interface. II. The general case.

PubMed

Dagastine, R R; White, L R

2002-03-15

The semianalytic theory developed previously (Chan, D. Y. C., Dagastine, R. R., and White, L. R., J. Colloid Interface Sci. 236, 141 (2001)) to predict the force curve of an AFM measurement at a liquid interface using a colloidal probe has been expanded to incorporate a general force law with both attractive and repulsive forces. Expressions for the gradient of the force curve are developed to calculate the point at which the probe particle on the cantilever will spontaneously jump in toward the liquid interface. The calculation of the jump instability is reduced to a straightforward embroidery of the simple algorithms presented in Chan et al. In a variety of sample calculations using force laws including van der Waals, electrostatic, and hydrophobic forces for both oil/water and bubble/water interfaces, we have duplicated the general behaviors observed in several AFM investigations at liquid interfaces. The behavior of the drop as a Hookean spring and the numerical difficulties of a full numerical calculation of F(deltaX) are also discussed.
Prevalence Comparison of Past-year Mental Disorders and Suicidal Behaviours in the Canadian Armed Forces and the Canadian General Population

PubMed Central

Zamorski, Mark A.; Boulos, David; Garber, Bryan G.

2016-01-01

Objective: Military personnel in Canada and elsewhere have been found to have higher rates of certain mental disorders relative to their corresponding general populations. However, published Canadian data have only adjusted for age and sex differences between the populations. Additional differences in the sociodemographic composition, labour force characteristics, and childhood trauma exposure in the populations could be driving these prevalence differences. Our objective is to compare the prevalence of past-year mental disorders and suicidal behaviours in the Canadian Armed Forces Regular Force with the rates in a representative, matched sample of Canadians in the general population (CGP). Methods: Data sources were the 2013 Canadian Forces Mental Health Survey and the 2012 Canadian Community Health Survey–Mental Health. CGP sample was restricted to match the age range, employment status, and history of chronic conditions of Regular Force personnel. An iterative proportional fitting method was used to approximate the marginal distribution of sociodemographic and childhood trauma variables in both samples. Results: Relative to the matched CGP, Regular Force personnel had significantly higher rates of past-year major depressive episode, generalized anxiety disorder, and suicide ideation. However, lower rates of alcohol use disorder were seen in Regular Force personnel relative to the matched CGP sample. Conclusions: Factors other than differences in sociodemographic composition and history of childhood trauma account for the excess burden of mental disorders and suicidal behaviours in the Canadian Armed Forces. Explanations to explore in future research include occupational trauma, selection effects, and differences in the context of administration of the 2 surveys. PMID:27270741
General view. View to southwest Offutt Air Force Base, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

General view. View to southwest - Offutt Air Force Base, Looking Glass Airborne Command Post, Vehicle Refueling Station, Northeast of AGE Storage Facility at far northwest end of Project Looking Glass Historic District, Bellevue, Sarpy County, NE
Defense Resource Management Study

DTIC Science & Technology

1979-02-01

exploit the fabrication and testing of experimental and proto- type hardware; it should not be permitted to increase reliance on design studies and... Nuclear Forces C. Forces for NATO D. Forces for Asia and the Pacific E. Forces for the Middle Ejst F. Forces for the Persian Gulf G. Theater... Nuclear Forces H. 1. J. General Purpose Forces Mobility Forces Land Forces K. Tactical Air Forces L. Use of U.S. Naval Forces for the Defense M
Modeling of control forces for kinematical constraints in the dynamics of multibody systems: A new approach

NASA Technical Reports Server (NTRS)

Ider, Sitki Kemal

1989-01-01

Conventionally kinematical constraints in multibody systems are treated similar to geometrical constraints and are modeled by constraint reaction forces which are perpendicular to constraint surfaces. However, in reality, one may want to achieve the desired kinematical conditions by control forces having different directions in relation to the constraint surfaces. The conventional equations of motion for multibody systems subject to kinematical constraints are generalized by introducing general direction control forces. Conditions for the selections of the control force directions are also discussed. A redundant robotic system subject to prescribed end-effector motion is analyzed to illustrate the methods proposed.
Marshall Space Flight Center Black History Month Program

NASA Image and Video Library

2018-02-21

The Black History Month program was presented at Marshall Space Flight Center with guest speaker Lt. General Stayce Harris. General Harris is the Inspector General of the Air Force and she is the first African American female Lieutenant General in the American military. The topic of her presentation was "African Americans in Times of War". The presentation was followed by an ethnic food sampling. General Harris is pictured here with local area Air Force JROTC cadets who attended the program.

Tough Tommy’s Space Force: General Thomas S. Power and the Air Force Space Program

DTIC Science & Technology

2016-06-01

public release by AU Security and Policy Review Office. TOUGH TOMMY’S SPACE FORCE GENERAL THOMAS S . POWER AND THE AIR FORCE SPACE PROGRAM BY...in 2007, a Master of Operational Art and Science from the Air Command and Staff College in 2015, and a Doctorate in Economic Development from New...without a college diploma, and a relic of a bygone era of barnstormers perhaps high on courage but low on intelligence.8 In history, Power was a “sadist
Force law in material media, hidden momentum and quantum phases

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

Kholmetskii, Alexander L., E-mail: alkholmetskii@gmail.com; Missevitch, Oleg V.; Yarman, T.

We address to the force law in classical electrodynamics of material media, paying attention on the force term due to time variation of hidden momentum of magnetic dipoles. We highlight that the emergence of this force component is required by the general theorem, deriving zero total momentum for any static configuration of charges/currents. At the same time, we disclose the impossibility to add this force term covariantly to the Lorentz force law in material media. We further show that the adoption of the Einstein–Laub force law does not resolve the issue, because for a small electric/magnetic dipole, the density ofmore » Einstein–Laub force integrates exactly to the same equation, like the Lorentz force with the inclusion of hidden momentum contribution. Thus, none of the available expressions for the force on a moving dipole is compatible with the relativistic transformation of force, and we support this statement with a number of particular examples. In this respect, we suggest applying the Lagrangian approach to the derivation of the force law in a magnetized/polarized medium. In the framework of this approach we obtain the novel expression for the force on a small electric/magnetic dipole, with the novel expression for its generalized momentum. The latter expression implies two novel quantum effects with non-topological phases, when an electric dipole is moving in an electric field, and when a magnetic dipole is moving in a magnetic field. These phases, in general, are not related to dynamical effects, because they are not equal to zero, when the classical force on a dipole is vanishing. The implications of the obtained results are discussed.« less
High Frontier, The Journal for Space & Missile Professionals. Volume 4, Number 4

DTIC Science & Technology

2008-08-01

46 Next Issue: Space Protection High Frontier Introduction General C . Robert Kehler Commander, Air Force Space Command “ The ... the Air Force and General C . Robert “Bob” Kehler (BS, Education, Pennsylvania State University; MS, Public Administra- tion, University of Oklahoma...depth interview with Dr. F. Robert Naka, former deputy director of the NRO (1969- 1972 ) and former chief scientist of the Air Force (1975-1978
The value of radiographs obtained during forced traction under general anaesthesia in predicting flexibility in idiopathic scoliosis with Cobb angles exceeding 60 degree.

PubMed

Ibrahim, T; Gabbar, O A; El-Abed, K; Hutchinson, M J; Nelson, I W

2008-11-01

Our aim in this prospective radiological study was to determine whether the flexibility rate calculated from radiographs obtained during forced traction under general anaesthesia, was better than that of fulcrum-bending radiographs before corrective surgery in predicting the extent of the available correction in patients with idiopathic scoliosis. We evaluated 33 patients with a Cobb angle > 60 degrees on a standing posteroanterior radiograph, who had been treated by posterior correction. Pre-operative standing fulcrum-bending radiographs and those with forced-traction under general anaesthesia were obtained. Post-operative standing radiographs were taken after surgical correction. The mean forced-traction flexibility rate was 55% (SD 11.3) which was significantly higher than the mean fulcrum-bending flexibility rate of 32% (SD 16.1) (p < 0.001). We found no correlation between either the forced-traction or fulcrum-bending flexibility rates and the correction rate post-operatively (p = 0.24 and p = 0.44, respectively). Radiographs obtained during forced traction under general anaesthesia were better at predicting the flexibility of the curve than fulcrum-bending radiographs in curves with a Cobb angle > 60 degrees in the standing position and may identify those patients for whom supplementary anterior surgery can be avoided.
Theory and computation of general force balance in non-axisymmetric tokamak equilibria

NASA Astrophysics Data System (ADS)

Park, Jong-Kyu; Logan, Nikolas; Wang, Zhirui; Kim, Kimin; Boozer, Allen; Liu, Yueqiang; Menard, Jonathan

2014-10-01

Non-axisymmetric equilibria in tokamaks can be effectively described by linearized force balance. In addition to the conventional isotropic pressure force, there are three important components that can strongly contribute to the force balance; rotational, anisotropic tensor pressure, and externally given forces, i.e. ∇ --> p + ρv-> . ∇ --> v-> + ∇ --> . <-->Π + f-> = j-> × B-> , especially in, but not limited to, high β and rotating plasmas. Within the assumption of nested flux surfaces, Maxwell equations and energy minimization lead to the modified-generalized Newcomb equation for radial displacements with simple algebraic relations for perpendicular and parallel displacements, including an inhomogeneous term if any of the forces are not explicitly dependent on displacements. The general perturbed equilibrium code (GPEC) solves this force balance consistent with energy and torque given by external perturbations. Local and global behaviors of solutions will be discussed when ∇ --> . <-->Π is solved by the semi-analytic code PENT and will be compared with MARS-K. Any first-principle transport code calculating ∇ --> . <-->Π or f-> , e.g. POCA, can also be incorporated without demanding iterations. This work was supported by DOE Contract DE-AC02-09CH11466.
Large General Purpose Frame for Studying Force Vectors

ERIC Educational Resources Information Center

Heid, Christy; Rampolla, Donald

2011-01-01

Many illustrations and problems on the vector nature of forces have weights and forces in a vertical plane. One of the common devices for studying the vector nature of forces is a horizontal "force table," in which forces are produced by weights hanging vertically and transmitted to cords in a horizontal plane. Because some students have…
14 CFR 25.143 - General.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false General. 25.143 Section 25.143 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... control forces permitted during the testing required by paragraph (a) through (c) of this section: Force...
A comparative study of single-leg ground reaction forces in running lizards.

PubMed

McElroy, Eric J; Wilson, Robbie; Biknevicius, Audrone R; Reilly, Stephen M

2014-03-01

The role of different limbs in supporting and propelling the body has been studied in many species with animals appearing to have either similarity in limb function or differential limb function. Differential hindlimb versus forelimb function has been proposed as a general feature of running with a sprawling posture and as benefiting sprawled postured animals by enhancing maneuvering and minimizing joint moments. Yet only a few species have been studied and thus the generality of differential limb function in running animals with sprawled postures is unknown. We measured the limb lengths of seven species of lizard and their single-limb three-dimensional ground reaction forces during high-speed running. We found that all species relied on the hindlimb for producing accelerative forces. Braking forces were forelimb dominated in four species and equally distributed between limbs in the other three. Vertical forces were dominated by the hindlimb in three species and equally distributed between the forelimb and hindlimb in the other four. Medial forces were dominated by the hindlimb in four species and equally distributed in the other three, with all Iguanians exhibiting hindlimb-biased medial forces. Relative hindlimb to forelimb length of each species was related to variation in hindlimb versus forelimb medial forces; species with relatively longer hindlimbs compared with forelimbs exhibited medial forces that were more biased towards the hindlimbs. These results suggest that the function of individual limbs in lizards varies across species with only a single general pattern (hindlimb-dominated accelerative force) being present.
The Wrong Target: The Problem of Mistargeting Resulting in Fratricide and Civilian Casualties

DTIC Science & Technology

2007-05-13

www.cbsnews.com/stories/2005/09/26/friendly/main886284.htm. on 21 January 2007. 47 Maurice Baril (General Canadian Air Force, Retired), President...Enduring Freedom and were your comrades-in- arms.”89 Canadian General Maurice Baril , in the final report on the Tarnak Farm incident, summarized...Techniques and Procedures Manual 3-1.5, (GPO 2006), pIV, 4-299. 88 General Maurice Baril (General Canadian Air Force, Retired), President Tarnak Farm
A Simple and Accurate Method To Calculate Free Energy Profiles and Reaction Rates from Restrained Molecular Simulations of Diffusive Processes.

PubMed

Ovchinnikov, Victor; Nam, Kwangho; Karplus, Martin

2016-08-25

A method is developed to obtain simultaneously free energy profiles and diffusion constants from restrained molecular simulations in diffusive systems. The method is based on low-order expansions of the free energy and diffusivity as functions of the reaction coordinate. These expansions lead to simple analytical relationships between simulation statistics and model parameters. The method is tested on 1D and 2D model systems; its accuracy is found to be comparable to or better than that of the existing alternatives, which are briefly discussed. An important aspect of the method is that the free energy is constructed by integrating its derivatives, which can be computed without need for overlapping sampling windows. The implementation of the method in any molecular simulation program that supports external umbrella potentials (e.g., CHARMM) requires modification of only a few lines of code. As a demonstration of its applicability to realistic biomolecular systems, the method is applied to model the α-helix ↔ β-sheet transition in a 16-residue peptide in implicit solvent, with the reaction coordinate provided by the string method. Possible modifications of the method are briefly discussed; they include generalization to multidimensional reaction coordinates [in the spirit of the model of Ermak and McCammon (Ermak, D. L.; McCammon, J. A. J. Chem. Phys. 1978, 69, 1352-1360)], a higher-order expansion of the free energy surface, applicability in nonequilibrium systems, and a simple test for Markovianity. In view of the small overhead of the method relative to standard umbrella sampling, we suggest its routine application in the cases where umbrella potential simulations are appropriate.
GAO's Views on the Default Task Force's Recommendations for Reducing Default Costs in the Guaranteed Student Loan Program. Testimony before the Subcommittee on Postsecondary Education, Committee on Education and Labor, House of Representatives.

ERIC Educational Resources Information Center

Gainer, William J.

This General Accounting Office (GAO) testimony before the Subcommittee on Postsecondary Education, Committee on Education and Labor, House of Representatives, concerns the findings of the task force that addressed the increasing costs of student loan defaults. The task force report is considered, generally, to provide additional incentives and…
Seeing Off the Bear: Anglo-American Air Power Cooperation During the Cold War,

DTIC Science & Technology

1995-01-01

Force History and Museums Program United States Air Force Washington, D.C. 1995 .ApprovAd fox r’Thiic r ~elease, j,, 117-~ I 7,CTh D Disbution...Air Power History Symposium began in late 1992 under the direction of General Bryce Poe II, President of the Air Force Historical Foundation, Air...vii Introduction and Welcome General Bryce Poe II; Air Marshal Sir Frederick Sowrey .............. 3 Opening
Molecular modeling of calmodulin: a comparison with crystallographic data

NASA Technical Reports Server (NTRS)

McDonald, J. J.; Rein, R.

1989-01-01

Two methods of side-chain placement on a modeled protein have been examined. Two molecular models of calmodulin were constructed that differ in the treatment of side chains prior to optimization of the molecule. A virtual bond analysis program developed by Purisima and Scheraga was used to determine the backbone conformation based on 2.2 angstroms resolution C alpha coordinates for the molecules. In the first model, side chains were initially constructed in an extended conformation. In the second model, a conformational grid search technique was employed. Calcium ions were treated explicitly during energy optimization using CHARMM. The models are compared to a recently published refined crystal structure of calmodulin. The results indicate that the initial choices for side-chains, but also significant effects on the main-chain conformation and supersecondary structure. The conformational differences are discussed. Analysis of these and other methods makes possible the formulation of a methodology for more appropriate side-chain placement in modeled proteins.
Web-Based Computational Chemistry Education with CHARMMing III: Reduction Potentials of Electron Transfer Proteins

PubMed Central

Perrin, B. Scott; Miller, Benjamin T.; Schalk, Vinushka; Woodcock, H. Lee; Brooks, Bernard R.; Ichiye, Toshiko

2014-01-01

A module for fast determination of reduction potentials, E°, of redox-active proteins has been implemented in the CHARMM INterface and Graphics (CHARMMing) web portal (www.charmming.org). The free energy of reduction, which is proportional to E°, is composed of an intrinsic contribution due to the redox site and an environmental contribution due to the protein and solvent. Here, the intrinsic contribution is selected from a library of pre-calculated density functional theory values for each type of redox site and redox couple, while the environmental contribution is calculated from a crystal structure of the protein using Poisson-Boltzmann continuum electrostatics. An accompanying lesson demonstrates a calculation of E°. In this lesson, an ionizable residue in a [4Fe-4S]-protein that causes a pH-dependent E° is identified, and the E° of a mutant that would test the identification is predicted. This demonstration is valuable to both computational chemistry students and researchers interested in predicting sequence determinants of E° for mutagenesis. PMID:25058418
Classical Molecular Dynamics with Mobile Protons.

PubMed

Lazaridis, Themis; Hummer, Gerhard

2017-11-27

An important limitation of standard classical molecular dynamics simulations is the inability to make or break chemical bonds. This restricts severely our ability to study processes that involve even the simplest of chemical reactions, the transfer of a proton. Existing approaches for allowing proton transfer in the context of classical mechanics are rather cumbersome and have not achieved widespread use and routine status. Here we reconsider the combination of molecular dynamics with periodic stochastic proton hops. To ensure computational efficiency, we propose a non-Boltzmann acceptance criterion that is heuristically adjusted to maintain the correct or desirable thermodynamic equilibria between different protonation states and proton transfer rates. Parameters are proposed for hydronium, Asp, Glu, and His. The algorithm is implemented in the program CHARMM and tested on proton diffusion in bulk water and carbon nanotubes and on proton conductance in the gramicidin A channel. Using hopping parameters determined from proton diffusion in bulk water, the model reproduces the enhanced proton diffusivity in carbon nanotubes and gives a reasonable estimate of the proton conductance in gramicidin A.
Motion and force control for multiple cooperative manipulators

NASA Technical Reports Server (NTRS)

Wen, John T.; Kreutz, Kenneth

1989-01-01

The motion and force control of multiple robot arms manipulating a commonly held object is addressed. A general control paradigm that decouples the motion and force control problems is introduced. For motion control, there are three natural choices: (1) joint torques, (2) arm-tip force vectors, and (3) the acceleration of a generalized coordinate. Choice (1) allows a class of relatively model-independent control laws by exploiting the Hamiltonian structure of the open-loop system; (2) and (3) require the full model information but produce simpler problems. To resolve the nonuniqueness of the joint torques, two methods are introduced. If the arm and object models are available, the allocation of the desired end-effector control force to the joint actuators can be optimized; otherwise the internal force can be controlled about some set point. It is shown that effective force regulation can be achieved even if little model information is available.
A Prototype JFACC: General George C. Kenney

DTIC Science & Technology

1994-06-01

Corps, as well as air forces from Australia and New Zealand . Many accounts of the Battles for Leyte and Luzon center around ground and naval forces...St Clair Streett USA Royal New Zealand Air Force (RNZAF) Royal Australian Air Force (RAAF) Air Command Organization SWPA June 15, 1944 Figure 5...Ground Task Force OPCON Operational Command POA Pacific Ocean Areas RAAF Royal Australian Air Force RNZAF Royal New Zealand Air Force SAP
The United States Air Force and Profession: Why Sixty Percent of Air Force General Officers are Still Pilots When Pilots Comprise Just Twenty Percent of the Officer Corps

DTIC Science & Technology

2006-08-25

EXA thog001uehMcoptr a acltetecus n pedo nm lnsi secnd. an dipath gide misila ad itereptrs o te trge fo detrutio anLreur intrcptos o hte I pefomin tes...a capability, at that time at least, to transmit video footage of the aircraft, then loiter while waiting for a decision to shoot down the aircraft or...emerges. In general, however, modem Air Force warfare takes on the aura of a video game. Furthermore, the air and missile crews do not generally see
General Aviation Task Force report

NASA Technical Reports Server (NTRS)

1993-01-01

General aviation is officially defined as all aviation except scheduled airlines and the military. It is the only air transportation to many communities throughout the world. In order to reverse the recent decline in general aviation aircraft produced in the United States, the Task Force recommends that NASA provide the expertise and facilities such as wind tunnels and computer codes for aircraft design. General aviation manufacturers are receptive to NASA's innovations and technological leadership and are expected to be effective users of NASA-generated technologies.
32 CFR 807.1 - General requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION SALE TO THE PUBLIC § 807.1 General requirements. (a) Unaltered Air Force publications and forms will be made available to the public with or without charge, subject to the requirements of this part. Base Chiefs of...

Army Task Force on Behavioral Health: Corrective Action Plan

DTIC Science & Technology

2013-01-01

Veterans Affairs Legal Section KNOWLEDGE MGMT SECTION • KMO • CAA Analyst Figure I-1. Task Force Organization. ACRONYM Key ASA(M&RA): Assistant...Army Audit Agency OTIG: Office of the Inspector General OTSG: Office of the Surgeon General KMO : Knowledge Management Officer CAA: Center for
14 CFR 25.143 - General.

Code of Federal Regulations, 2012 CFR

2012-01-01

... control forces permitted during the testing required by paragraph (a) through (c) of this section: Force... practices must be followed when demonstrating compliance with the control force limitations for short term... with the control force limitations for long term application that are prescribed in paragraph (d) of...
14 CFR 25.143 - General.

Code of Federal Regulations, 2011 CFR

2011-01-01

... control forces permitted during the testing required by paragraph (a) through (c) of this section: Force... practices must be followed when demonstrating compliance with the control force limitations for short term... with the control force limitations for long term application that are prescribed in paragraph (d) of...
14 CFR 25.143 - General.

Code of Federal Regulations, 2010 CFR

2010-01-01

... control forces permitted during the testing required by paragraph (a) through (c) of this section: Force... practices must be followed when demonstrating compliance with the control force limitations for short term... with the control force limitations for long term application that are prescribed in paragraph (d) of...
14 CFR 25.143 - General.

Code of Federal Regulations, 2013 CFR

2013-01-01

... control forces permitted during the testing required by paragraph (a) through (c) of this section: Force... practices must be followed when demonstrating compliance with the control force limitations for short term... with the control force limitations for long term application that are prescribed in paragraph (d) of...
Study of flutter related computational procedures for minimum weight structural sizing of advanced aircraft, supplemental data

NASA Technical Reports Server (NTRS)

Oconnell, R. F.; Hassig, H. J.; Radovcich, N. A.

1975-01-01

Computational aspects of (1) flutter optimization (minimization of structural mass subject to specified flutter requirements), (2) methods for solving the flutter equation, and (3) efficient methods for computing generalized aerodynamic force coefficients in the repetitive analysis environment of computer-aided structural design are discussed. Specific areas included: a two-dimensional Regula Falsi approach to solving the generalized flutter equation; method of incremented flutter analysis and its applications; the use of velocity potential influence coefficients in a five-matrix product formulation of the generalized aerodynamic force coefficients; options for computational operations required to generate generalized aerodynamic force coefficients; theoretical considerations related to optimization with one or more flutter constraints; and expressions for derivatives of flutter-related quantities with respect to design variables.
Dynamic Force Measurement with Strain Gauges

ERIC Educational Resources Information Center

Lee, Bruce E.

1974-01-01

Discusses the use of four strain gauges, a Wheatstone bridge, and an oscilloscope to measure forces dynamically. Included is an example of determining the centripetal force of a pendulum in a general physics laboratory. (CC)
Baryonic Force for Accelerated Cosmic Expansion and Generalized U1b Gauge Symmetry in Particle-Cosmology

NASA Astrophysics Data System (ADS)

Khan, Mehbub; Hao, Yun; Hsu, Jong-Ping

2018-01-01

Based on baryon charge conservation and a generalized Yang-Mills symmetry for Abelian (and non-Abelian) groups, we discuss a new baryonic gauge field and its linear potential for two point-like baryon charges. The force between two point-like baryons is repulsive, extremely weak and independent of distance. However, for two extended baryonic systems, we have a dominant linear force α r. Thus, only in the later stage of the cosmic evolution, when two baryonic galaxies are separated by an extremely large distance, the new repulsive baryonic force can overcome the gravitational attractive force. Such a model provides a gauge-field-theoretic understanding of the late-time accelerated cosmic expansion. The baryonic force can be tested by measuring the accelerated Wu-Doppler frequency shifts of supernovae at different distances.
Transient response of multidegree-of-freedom linear systems to forcing functions with inequality constraints

NASA Technical Reports Server (NTRS)

Michalopoulos, C. D.

1974-01-01

Optimal control theory is applied to analyze the transient response of discrete linear systems to forcing functions with unknown time dependence but having known bounds. Particular attention is given to forcing functions which include: (1) maximum displacement of any given mass element, (2) maximum relative displacement of any two adjacent masses, and (3) maximum acceleration of a given mass. Linear mechanical systems with an arbitrary number of degrees of freedom and only one forcing function acting are considered. In the general case, the desired forcing function is found to be a function that switches from the upper-to-lower bound and vice-versa at certain moments of time. A general procedure for finding such switching times is set forth.
GENERAL VIEW OF PUMPHOUSE FOUNDATIONS, ALSO SHOWING THREE PUMPS STILL ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

GENERAL VIEW OF PUMPHOUSE FOUNDATIONS, ALSO SHOWING THREE PUMPS STILL ON THE PAD, AND THE ELECTRICAL SUBSTATION IN LEFT MIDDLE DISTANCE - Edwards Air Force Base, Air Force Rocket Propulsion Laboratory, Flame Deflector Water System, Test Area 1-120, north end of Jupiter Boulevard, Boron, Kern County, CA
32 CFR 855.1 - Policy.

Code of Federal Regulations, 2013 CFR

2013-07-01

... of Air Force airfields in foreign countries will be subject to US Federal laws and regulations that... Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE AIRCRAFT CIVIL AIRCRAFT USE OF UNITED STATES AIR FORCE AIRFIELDS General Provisions § 855.1 Policy. The Air Force establishes and uses its...
32 CFR 855.1 - Policy.

Code of Federal Regulations, 2011 CFR

2011-07-01

... of Air Force airfields in foreign countries will be subject to US Federal laws and regulations that... Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE AIRCRAFT CIVIL AIRCRAFT USE OF UNITED STATES AIR FORCE AIRFIELDS General Provisions § 855.1 Policy. The Air Force establishes and uses its...
32 CFR 855.1 - Policy.

Code of Federal Regulations, 2012 CFR

2012-07-01

... of Air Force airfields in foreign countries will be subject to US Federal laws and regulations that... Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE AIRCRAFT CIVIL AIRCRAFT USE OF UNITED STATES AIR FORCE AIRFIELDS General Provisions § 855.1 Policy. The Air Force establishes and uses its...
32 CFR 855.1 - Policy.

Code of Federal Regulations, 2014 CFR

2014-07-01

... of Air Force airfields in foreign countries will be subject to US Federal laws and regulations that... Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE AIRCRAFT CIVIL AIRCRAFT USE OF UNITED STATES AIR FORCE AIRFIELDS General Provisions § 855.1 Policy. The Air Force establishes and uses its...
Inspector General, DoD, Oversight of the Air Force Audit Agency Audit of the FY 1996 Air Force Consolidated Financial Statements.

DTIC Science & Technology

1997-04-10

financial statements . We delegated the audit of the FY 1996 Air Force consolidated financial statements to the Air Force Audit Agency on May 17, 1996...This report provides our endorsement of the Air Force Audit Agency disclaimer of opinion on the Air Force consolidated financial statements for FY...1996, along with the Air Force Audit Agency Report of Audit, ’Opinion on Fiscal Year 1996 Air Force Consolidated Financial Statements .’
Wake Island, United States Territory General Environmental Compliance Assessment and Wastewater Characterization Survey.

DTIC Science & Technology

1998-04-01

Flight, 15th Civil Engineering Squadron, Hickam Air Force Base , Hawaii. The primary goals of this survey were to: 1. Provide a general environmental...2402 E Drive Brooks Air Force Base TX 78235-5114 W*C QTTALIT7 INSPECTED 4 NOTICES When Government drawings, specifications, or other data are used...time of this survey the real property assets of Wake Island were the responsibility of the US Air Force . Hickam AFB, Hawaii maintains the records for
Granular Contact Forces: Proof of "Self-Ergodicity" by Generalizing Boltzmann's Stosszahlansatz and H Theorem

NASA Technical Reports Server (NTRS)

Metzger, Philip T.

2006-01-01

Ergodicity is proved for granular contact forces. To obtain this proof from first principles, this paper generalizes Boltzmann's stosszahlansatz (molecular chaos) so that it maintains the necessary correlations and symmetries of granular packing ensembles. Then it formally counts granular contact force states and thereby defines the proper analog of Boltzmann's H functional. This functional is used to prove that (essentially) all static granular packings must exist at maximum entropy with respect to their contact forces. Therefore, the propagation of granular contact forces through a packing is a truly ergodic process in the Boltzmannian sense, or better, it is self-ergodic. Self-ergodicity refers to the non-dynamic, internal relationships that exist between the layer-by-layer and column-by-column subspaces contained within the phase space locus of any particular granular packing microstate. The generalized H Theorem also produces a recursion equation that may be solved numerically to obtain the density of single particle states and hence the distribution of granular contact forces corresponding to the condition of self-ergodicity. The predictions of the theory are overwhelmingly validated by comparison to empirical data from discrete element modeling.
7 CFR 1900.6 - Chair, Loan Resolution Task Force.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 12 2010-01-01 2010-01-01 false Chair, Loan Resolution Task Force. 1900.6 Section... AGRICULTURE PROGRAM REGULATIONS GENERAL Delegations of Authority § 1900.6 Chair, Loan Resolution Task Force. The Chair, Loan Resolution Task Force is delegated the following authorities, to be exercised until...
24 CFR 968.120 - Force account.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Force account. 968.120 Section 968... PUBLIC HOUSING MODERNIZATION General § 968.120 Force account. (a) For both CIAP and CGP, a PHA may undertake the activities using force account labor, only where specifically approved by HUD in the CIAP...
Environmental Assessment: General Plan-Based Environmental Impact Analysis Process, Laughlin Air Force Base

DTIC Science & Technology

2007-05-01

BASED ENVIROMENTAL IMPACT ANALYSIS PROCESS LAUGHLIN AIR FORCE BASE, TEXAS AGENCY: 47th Flying Training Wing (FTW), Laughlin Air Force Base (AFB), Texas...8217\\ \\ \\ \\ \\\\ \\ ~ >(- \\ , ~ AOC01 \\ PS018 / WP002 \\ DP008 // WP006 \\ ~ ,/ ’----- -----·-------------~--/·/ LAUGHLIN AIR FORCE BASE ENVIROMENTAL RESTORATION

1. GENERAL VIEW OF WEST FACE OF ENTRY CONTROL POINT ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. GENERAL VIEW OF WEST FACE OF ENTRY CONTROL POINT (BLDG. 768) SHOWING RELATIVE POSITION TO TECHNICAL SUPPORT BUILDING (BLDG. 762/762A) AND SLC-3 AIR FORCE BUILDING (BLDG. 761) - Vandenberg Air Force Base, Space Launch Complex 3, Entry Control Point, Napa & Alden Roads, Lompoc, Santa Barbara County, CA
14 CFR 1203b.104 - Exercise of arrest authority-general guidelines.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Exercise of arrest authority-general guidelines. 1203b.104 Section 1203b.104 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SECURITY PROGRAMS; ARREST AUTHORITY AND USE OF FORCE BY NASA SECURITY FORCE PERSONNEL § 1203b.104 Exercise...
14 CFR 1203b.104 - Exercise of arrest authority-general guidelines.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Exercise of arrest authority-general guidelines. 1203b.104 Section 1203b.104 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SECURITY PROGRAMS; ARREST AUTHORITY AND USE OF FORCE BY NASA SECURITY FORCE PERSONNEL § 1203b.104 Exercise...
14 CFR 1203b.104 - Exercise of arrest authority-general guidelines.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Exercise of arrest authority-general guidelines. 1203b.104 Section 1203b.104 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SECURITY PROGRAMS; ARREST AUTHORITY AND USE OF FORCE BY NASA SECURITY FORCE PERSONNEL § 1203b.104 Exercise...
14 CFR 1203b.104 - Exercise of arrest authority-general guidelines.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Exercise of arrest authority-general guidelines. 1203b.104 Section 1203b.104 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SECURITY PROGRAMS; ARREST AUTHORITY AND USE OF FORCE BY NASA SECURITY FORCE PERSONNEL § 1203b.104 Exercise...
Archimedes' Principle in General Coordinates

ERIC Educational Resources Information Center

Ridgely, Charles T.

2010-01-01

Archimedes' principle is well known to state that a body submerged in a fluid is buoyed up by a force equal to the weight of the fluid displaced by the body. Herein, Archimedes' principle is derived from first principles by using conservation of the stress-energy-momentum tensor in general coordinates. The resulting expression for the force is…
32 CFR 865.5 - Decision of the Secretary of the Air Force.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 6 2010-07-01 2010-07-01 false Decision of the Secretary of the Air Force. 865.5 Section 865.5 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ORGANIZATION AND MISSION-GENERAL PERSONNEL REVIEW BOARDS Air Force Board for Correction of Military Records...
Inspector General, DOD, Oversight of the Air Force Audit Agency Audit of the FY 1995 Air Force Consolidated Financial Statements.

DTIC Science & Technology

1996-04-18

financial statements . We delegated the audit of the FY 1995 Air Force consolidated financial statements to the Air Force Audit Agency. On March 1...1996, the Air Force Audit Agency issued its "Report of Audit: Opinion on Fiscal Year 1995 Air Force Consolidated Financial Statements " (Project 94053001...disclaimer of opinion. The audit objective was to determine the accuracy and completeness of the audit of the FY 1995 Air Force consolidated financial statements conducted
General Electric Unattended Power System Study. Addendum

DTIC Science & Technology

1980-05-01

AND NAVIGATION SYSTEMS ELECTRONIC SYSTEMS DIVISION AIR FORCE SYSTEMS COMMAND UNITED STATES AIR FORCE Hascom Air Force Base, Massachusetts DTIC C-3 B I...MITRE Corporation under Project No. 633A. The contract is sponsored by the Electronic Systems *Division, Air Force Systems Command, Hanscom Air Force...is delivered fully integrated, tested, and certified. The system consists of a combustion system, vapor generator, turbo- alternator, air -cooled
Solar Influences on El Nino/Southern Oscillation Dynamics Over the Last Millennium

NASA Astrophysics Data System (ADS)

Stevenson, S.; Capotondi, A.; Fasullo, J.; Otto-Bliesner, B. L.

2017-12-01

The El Niño/Southern Oscillation (ENSO) exhibits considerable differences between the evolution of individual El Nino and La Nina events (`ENSO diversity'), with significant implications for impacts studies. However, the degree to which external forcing may affect ENSO diversity is not well understood, due to both internal variability and potentially compensatory contributions from multiple forcings. The Community Earth System Model Last Millennium Ensemble (CESM LME) provides an ideal testbed for studying the sensitivity of twentieth century ENSO to forced climate changes, as it contains many realizations of the 850-2005 period with differing combinations of forcings. Metrics of ENSO amplitude and diversity are compared across LME simulations, and although forced changes to ENSO amplitude are generally small, forced changes to diversity are often detectable. Anthropogenic changes to greenhouse gas and ozone/aerosol emissions modify the persistence of Eastern and Central Pacific El Nino events, through shifts in the upwelling and zonal advective feedbacks; these influences generally cancel one another over the twentieth century. Natural forcings are generally small over the 20th century, but when epochs of high/low solar irradiance are compared, distinct shifts in the development and termination of El Nino events can be observed. This indicates that solar variability can indeed have a significant role to play in setting the characteristics of tropical Pacific climate variability. Implications for configuring and evaluating projections of future climate change will be discussed.
Consistent forcing scheme in the cascaded lattice Boltzmann method

NASA Astrophysics Data System (ADS)

Fei, Linlin; Luo, Kai Hong

2017-11-01

In this paper, we give an alternative derivation for the cascaded lattice Boltzmann method (CLBM) within a general multiple-relaxation-time (MRT) framework by introducing a shift matrix. When the shift matrix is a unit matrix, the CLBM degrades into an MRT LBM. Based on this, a consistent forcing scheme is developed for the CLBM. The consistency of the nonslip rule, the second-order convergence rate in space, and the property of isotropy for the consistent forcing scheme is demonstrated through numerical simulations of several canonical problems. Several existing forcing schemes previously used in the CLBM are also examined. The study clarifies the relation between MRT LBM and CLBM under a general framework.
Why do things fall? How to explain why gravity is not a force

NASA Astrophysics Data System (ADS)

Stannard, Warren B.

2018-03-01

In most high school physics classes, gravity is described as an attractive force between two masses as formulated by Newton over 300 years ago. Einstein’s general theory of relativity implies that gravitational effects are instead the result of a ‘curvature’ of space-time. However, explaining why things fall without resorting to Newton’s gravitational force can be difficult. This paper introduces some simple graphical and visual analogies and models which are suitable for the introduction of Einstein’s theory of general relativity at a high school level. These models provide an alternative to Newton’s gravitational force and help answer the simple question: why do things fall?
Reductions in U.S. Costs to Station Forces in the Federal Republic of Germany and the United Kingdom Are Unlikely.

DTIC Science & Technology

1984-07-31

AD-A144 501 REDUCTIONS IN US COSTS TO STATION FORCES IN THE FEDERAL i/’i REPUBLIC OF GERMA..(U) GENERAL ACCOUNTING OFFICE WASHINGTON DC RESOURCES...COMPTROLLER GENERAL Report To The Chairman Subcommittee On Defense, Senate p Committee On Appropriations OF THE UNITED STATES 0 lot Reductions In U.S. Costs To...reducing the costs of sta- tioning U.S. Forces in Europe through in- creased cost sharing by the European allies. The Federal Republic of Germany and
The significance of cloud-radiative forcing to the general circulation on climate time scales - A satellite interpretation

NASA Technical Reports Server (NTRS)

Sohn, Byung-Ju; Smith, Eric A.

1992-01-01

This paper focuses on the role of cloud- and surface-atmosphere forcing on the net radiation balance and their potential impact on the general circulation at climate time scales. The globally averaged cloud-forcing estimates and cloud sensitivity values taken from various recent studies are summarized. It is shown that the net radiative heating over the tropics is principally due to high clouds, while the net cooling in mid- and high latitudes is dominated by low and middle clouds.
Generalization of the quasi-geostrophic Eliassen-Palm flux to include eddy forcing of condensation heating

NASA Technical Reports Server (NTRS)

Stone, P. H.; Salustri, G.

1984-01-01

A modified Eulerian form of the Eliassen-Palm flux which includes the effect of eddy forcing on condensation heating is defined. With the two-dimensional vector flux in the meridional plane which is a function of the zonal mean eddy fluxes replaced by the modified flux, both the Eliassen-Palm theorem and a modified but more general form of the nonacceleration theorem for quasi-geostrophic motion still hold. Calculations of the divergence of the modified flux and of the eddy forcing of the moisture field are presented.
MAJOR GENERAL PETER E. GERSTEN > U.S. Air Force > Biography Display

Science.gov Websites

Speeches Archive Former AF Top 3 Viewpoints and Speeches Air Force Warrior Games 2017 Events 2018 Air Force Strategic Documents Desert Storm 25th Anniversary Observances DoD Warrior Games Portraits in Courage
14 CFR § 1203b.104 - Exercise of arrest authority-general guidelines.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 5 2014-01-01 2014-01-01 false Exercise of arrest authority-general guidelines. Â§ 1203b.104 Section Â§ 1203b.104 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SECURITY PROGRAMS; ARREST AUTHORITY AND USE OF FORCE BY NASA SECURITY FORCE PERSONNEL § 1203b.104...
The Evolution of General Education Requirements at Prince George's Community College.

ERIC Educational Resources Information Center

Barshay, Robert; Cant, Catherine

In August 1981, a task force was created at Maryland's Prince George's Community College (PGCC) to analyze the college's General Education (GE) requirements in terms of their appropriateness as a major component of Associate Degree (AD) programs. Rather than increase the number of GE requirements, the task force sought to identify the skills,…
32 CFR Appendix D to Part 806b - General and Specific Exemptions

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 6 2012-07-01 2012-07-01 false General and Specific Exemptions D Appendix D to Part 806b National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION... systems of records maintained by the Department of the Air Force shall be exempt from the requirements of...
32 CFR Appendix D to Part 806b - General and Specific Exemptions

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 6 2011-07-01 2011-07-01 false General and Specific Exemptions D Appendix D to Part 806b National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION... systems of records maintained by the Department of the Air Force shall be exempt from the requirements of...

32 CFR Appendix D to Part 806b - General and Specific Exemptions

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 6 2013-07-01 2013-07-01 false General and Specific Exemptions D Appendix D to Part 806b National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION... systems of records maintained by the Department of the Air Force shall be exempt from the requirements of...
Analysis of the vibratory excitation arising from spiral bevel gears

NASA Technical Reports Server (NTRS)

Mark, William D.

1987-01-01

Tools required to understand and predict in terms of its underlying causes the vibratory excitation arising from meshing spiral bevel gears are developed. A generalized three component transmission error of meshing spiral bevel gears is defined. Equations are derived that yield the three components of the generalized transmission error in terms of deviations of tooth running surfaces from equispaced perfect spherical involute surfaces and tooth/gearbody elastic deformations arising from the three components of the generalized force transmitted by the meshing gears. A method for incorporating these equations into the equations of motion of a gear system is described. Equations are derived for the three components of the generalized force transmitted by the gears which are valid whenever inertial effects of the meshing gears and their supports are negligible. Bearing offsets from the positions occupied by the shaft centerlines of perfect spherical involute bevel gears and bearing/bearing support flexibilities enter into the computation of these forces.
Optical force on a large sphere illuminated by Bessel beams: comparisons between ray optics method and generalized Lorenz-Mie theory.

PubMed

Song, Shukun; Wang, Neng; Lu, Wanli; Lin, Zhifang

2014-10-01

Optical forces are calculated for a dielectric spherical particle illuminated by a zero-order Bessel beam based on both the generalized Lorenz-Mie theory (GLMT) and the ray optics method (ROM). Particles with positive and negative refractive indices are examined. The peculiar characteristics of the Bessel beam allow for analytical expressions for the beam shape coefficients required in the GLMT as well as a decomposition of optical force into the gradient and the scattering forces irrespective of the particle size, which enable respective comparisons for the gradient and scattering forces between the results obtained from the GLMT and the ROM. Our results demonstrate that the discrepancy between the results obtained from the GLMT and the ROM depends on the particle refractive index n_p, the particle size, and, also, the particle location in the beam field. As the particle size increases, the difference between the results from the GLMT and the ROM shows a general tendency of decreasing, as can be expected, but the change may exhibit oscillatory rather than monotonic behavior. A phase diagram is presented that displays the regime for particle size and refractive index where a specified accuracy can be achieved for optical force by the ROM.
10 CFR 1049.7 - Exercise of arrest authority-Use of deadly force.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 4 2012-01-01 2012-01-01 false Exercise of arrest authority-Use of deadly force. 1049.7 Section 1049.7 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS OF THE STRATEGIC PETROLEUM RESERVE § 1049.7 Exercise of arrest authority...
10 CFR 1049.7 - Exercise of arrest authority-Use of deadly force.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 4 2013-01-01 2013-01-01 false Exercise of arrest authority-Use of deadly force. 1049.7 Section 1049.7 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS OF THE STRATEGIC PETROLEUM RESERVE § 1049.7 Exercise of arrest authority...
10 CFR 1049.7 - Exercise of arrest authority-Use of deadly force.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 4 2014-01-01 2014-01-01 false Exercise of arrest authority-Use of deadly force. 1049.7 Section 1049.7 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS OF THE STRATEGIC PETROLEUM RESERVE § 1049.7 Exercise of arrest authority...
10 CFR 1049.7 - Exercise of arrest authority-Use of deadly force.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false Exercise of arrest authority-Use of deadly force. 1049.7 Section 1049.7 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS OF THE STRATEGIC PETROLEUM RESERVE § 1049.7 Exercise of arrest authority...
10 CFR 1049.7 - Exercise of arrest authority-Use of deadly force.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Exercise of arrest authority-Use of deadly force. 1049.7 Section 1049.7 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED ARREST AUTHORITY AND USE OF FORCE BY PROTECTIVE FORCE OFFICERS OF THE STRATEGIC PETROLEUM RESERVE § 1049.7 Exercise of arrest authority...
Handling Quality Requirements for Advanced Aircraft Design: Longitudinal Mode

DTIC Science & Technology

1979-08-01

phases of air -to- air combat, for example). This is far simpler than the general problem of control law definition. How- ever, the results of such...unlimited. Ali FORCE FUGHT DYNAMICS LABORATORYAIR FORCE WRIGHT AERONAUTICALLABORATORIES AIR FORCE SYSTEMS COMMANDI * WRIGHT-PATITERSON AIR FORCE BASE...not necessarily shared by the Air Force. Brian. W. VauVliet Project Engineer S Rorad0. Anderson, Chief Control Dynamics Branch Flight Control Division
The Prussian German General Staff System and Its Impact on the General and Admiral Staff Officers of the Federal Armed Forces of Today

DTIC Science & Technology

1991-03-15

General-and six ministerial divisions-- the Budget Division, the Personnel Management Division, the Quartering, Real Estate and Construction Division and... Management Division, 39,242 officers served in the Bundeswehr during the first half of the eighties: 26,102 regular line officers (Truppenoffiziere), 1,615...additionally attend a 6 months language course 17 Camand and leadeship doctrine, seaity policy and a=ed forces ard social sciences. in a fourth area, single
47 CFR 2.100 - International regulations in force.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false International regulations in force. 2.100 Section 2.100 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL FREQUENCY ALLOCATIONS AND RADIO....100 International regulations in force. The ITU Radio Regulations, edition of 2004, have been...
A comparison of morbidity in the Australian Defence Force with Australian general practice.

PubMed

Neath, A T; Quail, G G

2001-01-01

This study was designed to examine morbidity patterns among Australian Defence Forces members and to compare them with civilian general practice. The study was conducted in the outpatient departments of the Royal Australian Air Force (RAAF) No. 6 Hospital, Melbourne, Australia. The patients studied were male and female members of the RAAF (66%), Army (25%), and Navy (9%). The problems managed at all primary care consultations during 1993 and 1994 were coded using the Ninth Revision of the International Classification of Diseases (Clinical Modification). The codes were grouped and compared against a major study of Australian general practice. In the 6 Hospital study, 21,910 problems were managed at 19,909 consultations. The main differences found between the two studies were that service personnel had more medical examinations, more musculoskeletal and respiratory problems, and fewer psychological and cardiovascular problems. Most of the differences observed may reflect the Defence Force's recruitment selection criteria and the emphasis on physical fitness and diet.
The formulation of dynamical contact problems with friction in the case of systems of rigid bodies and general discrete mechanical systems—Painlevé and Kane paradoxes revisited

NASA Astrophysics Data System (ADS)

Charles, Alexandre; Ballard, Patrick

2016-08-01

The dynamics of mechanical systems with a finite number of degrees of freedom (discrete mechanical systems) is governed by the Lagrange equation which is a second-order differential equation on a Riemannian manifold (the configuration manifold). The handling of perfect (frictionless) unilateral constraints in this framework (that of Lagrange's analytical dynamics) was undertaken by Schatzman and Moreau at the beginning of the 1980s. A mathematically sound and consistent evolution problem was obtained, paving the road for many subsequent theoretical investigations. In this general evolution problem, the only reaction force which is involved is a generalized reaction force, consistently with the virtual power philosophy of Lagrange. Surprisingly, such a general formulation was never derived in the case of frictional unilateral multibody dynamics. Instead, the paradigm of the Coulomb law applying to reaction forces in the real world is generally invoked. So far, this paradigm has only enabled to obtain a consistent evolution problem in only some very few specific examples and to suggest numerical algorithms to produce computational examples (numerical modeling). In particular, it is not clear what is the evolution problem underlying the computational examples. Moreover, some of the few specific cases in which this paradigm enables to write down a precise evolution problem are known to show paradoxes: the Painlevé paradox (indeterminacy) and the Kane paradox (increase in kinetic energy due to friction). In this paper, we follow Lagrange's philosophy and formulate the frictional unilateral multibody dynamics in terms of the generalized reaction force and not in terms of the real-world reaction force. A general evolution problem that governs the dynamics is obtained for the first time. We prove that all the solutions are dissipative; that is, this new formulation is free of Kane paradox. We also prove that some indeterminacy of the Painlevé paradox is fixed in this formulation.
Mean-force-field and mean-spherical approximations for the electric microfield distribution at a charged point in the charged-hard-particles fluid

NASA Astrophysics Data System (ADS)

Rosenfeld, Yaakov

1989-01-01

The linearized mean-force-field approximation, leading to a Gaussian distribution, provides an exact formal solution to the mean-spherical integral equation model for the electric microfield distribution at a charged point in the general charged-hard-particles fluid. Lado's explicit solution for plasmas immediately follows this general observation.
A Potential Theory for the Steady Separated Flow about an Aerofoil Section

DTIC Science & Technology

1988-02-01

Adviser (3 copies Doc Data sheet) Aircraft Maintenance and Flight Trials Unit Director of Naval Aircraft Engineering Director of Naval Air Warfare...Superintendent, Aircraft Maintenance and Repair Army Office Scientific Adviser - Army (Doc Data sheet only) Engineering Development Establishment, Library...Flight Group Library Technical Division Library Director General Aircraft Engineering - Air Force Director General Operational Requirements - Air Force
General Cognitive Ability Predicts Job Performance. Interim Technical Paper for Period November 1990 - November 1991.

ERIC Educational Resources Information Center

Ree, Malcolm James; And Others

A study investigated the roles of general ability and specific abilities as predictors of several job performance criteria for Air Force enlistees in eight jobs. Subjects were 1,545 Air Force enlistees entering from 1984 through 1988 who had tested with the Armed Services Vocational Aptitude Battery (ASVAB) parallel forms 11, 12, or 13. Subjects…
32 CFR 231.4 - General provisions.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., TN 38055-3120. (iii) For addresses of Department of the Air Force active, retired, separated and civilian personnel, financial institutions may telephone (210) 565-2660 or write to: Air Force Personnel... prevents use of the Armed Forces Radio and Television Service to promote a specific financial institution...
Practical Considerations for Using Constant Force Springs in Space-Based Mechanisms

NASA Technical Reports Server (NTRS)

Williams, R. Brett; Fisher, Charles D.; Gallon, John C.

2013-01-01

Mechanical springs are a common element in mechanism from all walks of life; cars, watches, appliances, and many others. These springs generally exhibit a linear relationship between force and deflection. In small mechanisms, deflections are small so the variation in spring force between one position and another are generally small and do not influence the design or functionality of the device. However, as the spacecraft industry drives towards larger, deployable satellites, the distances a spring or springs must function over can become considerable so much so that the structural integrity of the device may be impacted. As such, an increasingly common mechanism element is the constant force spring- one that provides a constant force regardless of deflection. These elements are commonly in the conceptual design phase to deal with system-level large deflections, but in the detailed design or integration test phase they can pose significant implementation issues. This article addresses some of the detailed issues in order for these constant force springs to be properly designed into space systems.
Magnetodynamic stability of a fluid cylinder under the Lundquist force-free magnetic field

NASA Astrophysics Data System (ADS)

Radwan, Ahmed E.; Halawa, Mohamed A.

1990-04-01

The magnetodynamic (in)stability of a conducting fluid cylinder subject to the capillarity and electromagnetic forces has been developed. The cylinder is pervaded by a uniform magnetic field but embedded in the Lundquist force-free varying field that allows for flowing a current surrounding the fluid. A general eigenvalue relation is derived based on a study of the equilibrium and perturbed states. The stability criterion is discussed analytically in general terms. The surface tension is destabilizing for small axisymmetric mode and stable for all others. The principle of the exchange of stability is allowed for the present problem due to the non-uniform behavior of the force-free field. Each of the axial and transverse force-free fields separately exerts a stabilizing influence in the most dangerous mode but the combined contribution of them is strongly destabilizing. Whether the model is acted upon the electromagnetic force (with the Lundquist field) the stability restrictions or/and the capillarity force are identified. Several reported works can be recovered as limiting cases with appropriate simplifications.
Response of discrete linear systems to forcing functions with inequality constraints.

NASA Technical Reports Server (NTRS)

Michalopoulos, C. D.; Riley, T. A.

1972-01-01

An analysis is made of the maximum response of discrete, linear mechanical systems to arbitrary forcing functions which lie within specified bounds. Primary attention is focused on the complete determination of the forcing function which will engender maximum displacement to any particular mass element of a multi-degree-of-freedom system. In general, the desired forcing function is found to be a bang-bang type function, i.e., a function which switches from the maximum to the minimum bound and vice-versa at certain instants of time. Examples of two-degree-of-freedom systems, with and without damping, are presented in detail. Conclusions are drawn concerning the effect of damping on the switching times and the general procedure for finding these times is discussed.

Modeling, molecular dynamics, and docking assessment of transcription factor rho: a potential drug target in Brucella melitensis 16M

PubMed Central

Pradeepkiran, Jangampalli Adi; Kumar, Konidala Kranthi; Kumar, Yellapu Nanda; Bhaskar, Matcha

2015-01-01

The zoonotic disease brucellosis, a chronic condition in humans affecting renal and cardiac systems and causing osteoarthritis, is caused by Brucella, a genus of Gram-negative, facultative, intracellular pathogens. The mode of transmission and the virulence of the pathogens are still enigmatic. Transcription regulatory elements, such as rho proteins, play an important role in the termination of transcription and/or the selection of genes in Brucella. Adverse effects of the transcription inhibitors play a key role in the non-successive transcription challenges faced by the pathogens. In the investigation presented here, we computationally predicted the transcription termination factor rho (TtFRho) inhibitors against Brucella melitensis 16M via a structure-based method. In view the unknown nature of its crystal structure, we constructed a robust three-dimensional homology model of TtFRho’s structure by comparative modeling with the crystal structure of the Escherichia coli TtFRho (Protein Data Bank ID: 1PVO) as a template in MODELLER (v 9.10). The modeled structure was optimized by applying a molecular dynamics simulation for 2 ns with the CHARMM (Chemistry at HARvard Macromolecular Mechanics) 27 force field in NAMD (NAnoscale Molecular Dynamics program; v 2.9) and then evaluated by calculating the stereochemical quality of the protein. The flexible docking for the interaction phenomenon of the template consists of ligand-related inhibitor molecules from the ZINC (ZINC Is Not Commercial) database using a structure-based virtual screening strategy against minimized TtFRho. Docking simulations revealed two inhibitors compounds – ZINC24934545 and ZINC72319544 – that showed high binding affinity among 2,829 drug analogs that bind with key active-site residues; these residues are considered for protein-ligand binding and unbinding pathways via steered molecular dynamics simulations. Arg215 in the model plays an important role in the stability of the protein-ligand complex via a hydrogen bonding interaction by aromatic-π contacts, and the ADMET (absorption, distribution, metabolism, and excretion) analysis of best leads indicate nontoxic in nature with good potential for drug development. PMID:25848225
Homology modeling and docking studies of a Δ9-fatty acid desaturase from a Cold-tolerant Pseudomonas sp. AMS8

PubMed Central

Garba, Lawal; Mohamad Yussoff, Mohamad Ariff; Abd Halim, Khairul Bariyyah; Ishak, Siti Nor Hasmah; Mohamad Ali, Mohd Shukuri; Oslan, Siti Nurbaya

2018-01-01

Membrane-bound fatty acid desaturases perform oxygenated desaturation reactions to insert double bonds within fatty acyl chains in regioselective and stereoselective manners. The Δ9-fatty acid desaturase strictly creates the first double bond between C9 and 10 positions of most saturated substrates. As the three-dimensional structures of the bacterial membrane fatty acid desaturases are not available, relevant information about the enzymes are derived from their amino acid sequences, site-directed mutagenesis and domain swapping in similar membrane-bound desaturases. The cold-tolerant Pseudomonas sp. AMS8 was found to produce high amount of monounsaturated fatty acids at low temperature. Subsequently, an active Δ9-fatty acid desaturase was isolated and functionally expressed in Escherichia coli. In this paper we report homology modeling and docking studies of a Δ9-fatty acid desaturase from a Cold-tolerant Pseudomonas sp. AMS8 for the first time to the best of our knowledge. Three dimensional structure of the enzyme was built using MODELLER version 9.18 using a suitable template. The protein model contained the three conserved-histidine residues typical for all membrane-bound desaturase catalytic activity. The structure was subjected to energy minimization and checked for correctness using Ramachandran plots and ERRAT, which showed a good quality model of 91.6 and 65.0%, respectively. The protein model was used to preform MD simulation and docking of palmitic acid using CHARMM36 force field in GROMACS Version 5 and Autodock tool Version 4.2, respectively. The docking simulation with the lowest binding energy, −6.8 kcal/mol had a number of residues in close contact with the docked palmitic acid namely, Ile26, Tyr95, Val179, Gly180, Pro64, Glu203, His34, His206, His71, Arg182, Thr85, Lys98 and His177. Interestingly, among the binding residues are His34, His71 and His206 from the first, second, and third conserved histidine motif, respectively, which constitute the active site of the enzyme. The results obtained are in compliance with the in vivo activity of the Δ9-fatty acid desaturase on the membrane phospholipids. PMID:29576935
Molecular Dynamics Studies of Polyethylene Oxide and Polyethylene Glycol: Hydrodynamic Radius and Shape Anisotropy

PubMed Central

Lee, Hwankyu; Venable, Richard M.; MacKerell, Alexander D.; Pastor, Richard W.

2008-01-01

A revision (C35r) to the CHARMM ether force field is shown to reproduce experimentally observed conformational populations of dimethoxyethane. Molecular dynamics simulations of 9, 18, 27, and 36-mers of polyethylene oxide (PEO) and 27-mers of polyethylene glycol (PEG) in water based on C35r yield a persistence length λ = 3.7 Å, in quantitative agreement with experimentally obtained values of 3.7 Å for PEO and 3.8 Å for PEG; agreement with experimental values for hydrodynamic radii of comparably sized PEG is also excellent. The exponent υ relating the radius of gyration and molecular weight (\\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}R_{{\\mathrm{g}}}{\\propto}M_{{\\mathrm{w}}}^{{\\upsilon}}\\end{equation*}\\end{document}) of PEO from the simulations equals 0.515 ± 0.023, consistent with experimental observations that low molecular weight PEG behaves as an ideal chain. The shape anisotropy of hydrated PEO is 2.59:1.44:1.00. The dimension of the middle length for each of the polymers nearly equals the hydrodynamic radius \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}R_{{\\mathrm{h}}}\\end{equation*}\\end{document}obtained from diffusion measurements in solution. This explains the correspondence of \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}R_{{\\mathrm{h}}}\\end{equation*}\\end{document} and \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}R_{{\\mathrm{p}}},\\end{equation*}\\end{document} the pore radius of membrane channels: a polymer such as PEG diffuses with its long axis parallel to the membrane channel, and passes through the channel without substantial distortion. PMID:18456821
Stability analysis of multiple-robot control systems

NASA Technical Reports Server (NTRS)

Wen, John T.; Kreutz, Kenneth

1989-01-01

In a space telerobotic service scenario, cooperative motion and force control of multiple robot arms are of fundamental importance. Three paradigms to study this problem are proposed. They are distinguished by the set of variables used for control design. They are joint torques, arm tip force vectors, and an accelerated generalized coordinate set. Control issues related to each case are discussed. The latter two choices require complete model information, which presents practical modeling, computational, and robustness problems. Therefore, focus is on the joint torque control case to develop relatively model independent motion and internal force control laws. The rigid body assumption allows the motion and force control problems to be independently addressed. By using an energy motivated Lyapunov function, a simple proportional derivative plus gravity compensation type of motion control law is always shown to be stabilizing. The asymptotic convergence of the tracing error to zero requires the use of a generalized coordinate with the contact constraints taken into account. If a non-generalized coordinate is used, only convergence to a steady state manifold can be concluded. For the force control, both feedforward and feedback schemes are analyzed. The feedback control, if proper care has been taken, exhibits better robustness and transient performance.
Theory of orthodontic motions

NASA Technical Reports Server (NTRS)

Pepe, S.; Pepe, W. D.; Strauss, A. M.

1976-01-01

A general theory of orthodontic motion is developed that can be applied to determine the forces necessary to induce a given tooth to move to the predetermined desirable position. It is assumed that the natural (nonorthodontic) forces may be represented by a periodic function and the orthodontic forces may be superimposed upon the natural forces. A simple expression is derived for the applied stress.
Dimensional reduction of a general advection–diffusion equation in 2D channels

NASA Astrophysics Data System (ADS)

Kalinay, Pavol; Slanina, František

2018-06-01

Diffusion of point-like particles in a two-dimensional channel of varying width is studied. The particles are driven by an arbitrary space dependent force. We construct a general recurrence procedure mapping the corresponding two-dimensional advection-diffusion equation onto the longitudinal coordinate x. Unlike the previous specific cases, the presented procedure enables us to find the one-dimensional description of the confined diffusion even for non-conservative (vortex) forces, e.g. caused by flowing solvent dragging the particles. We show that the result is again the generalized Fick–Jacobs equation. Despite of non existing scalar potential in the case of vortex forces, the effective one-dimensional scalar potential, as well as the corresponding quasi-equilibrium and the effective diffusion coefficient can be always found.
A generalized modal shock spectra method for spacecraft loads analysis

NASA Technical Reports Server (NTRS)

Trubert, M.; Salama, M.

1979-01-01

Unlike the traditional shock spectra approach, the generalization presented in this paper permits elastic interaction between the spacecraft and launch vehicle in order to obtain accurate bounds on the spacecraft response and structural loads. In addition, the modal response from a previous launch vehicle transient analysis - with or without a dummy spacecraft - is exploited in order to define a modal impulse as a simple idealization of the actual forcing function. The idealized modal forcing function is then used to derive explicit expressions for an estimate of the bound on the spacecraft structural response and forces.
Web-Based Computational Chemistry Education with CHARMMing I: Lessons and Tutorial

PubMed Central

Miller, Benjamin T.; Singh, Rishi P.; Schalk, Vinushka; Pevzner, Yuri; Sun, Jingjun; Miller, Carrie S.; Boresch, Stefan; Ichiye, Toshiko; Brooks, Bernard R.; Woodcock, H. Lee

2014-01-01

This article describes the development, implementation, and use of web-based “lessons” to introduce students and other newcomers to computer simulations of biological macromolecules. These lessons, i.e., interactive step-by-step instructions for performing common molecular simulation tasks, are integrated into the collaboratively developed CHARMM INterface and Graphics (CHARMMing) web user interface (http://www.charmming.org). Several lessons have already been developed with new ones easily added via a provided Python script. In addition to CHARMMing's new lessons functionality, web-based graphical capabilities have been overhauled and are fully compatible with modern mobile web browsers (e.g., phones and tablets), allowing easy integration of these advanced simulation techniques into coursework. Finally, one of the primary objections to web-based systems like CHARMMing has been that “point and click” simulation set-up does little to teach the user about the underlying physics, biology, and computational methods being applied. In response to this criticism, we have developed a freely available tutorial to bridge the gap between graphical simulation setup and the technical knowledge necessary to perform simulations without user interface assistance. PMID:25057988
Web-based computational chemistry education with CHARMMing I: Lessons and tutorial.

PubMed

Miller, Benjamin T; Singh, Rishi P; Schalk, Vinushka; Pevzner, Yuri; Sun, Jingjun; Miller, Carrie S; Boresch, Stefan; Ichiye, Toshiko; Brooks, Bernard R; Woodcock, H Lee

2014-07-01

This article describes the development, implementation, and use of web-based "lessons" to introduce students and other newcomers to computer simulations of biological macromolecules. These lessons, i.e., interactive step-by-step instructions for performing common molecular simulation tasks, are integrated into the collaboratively developed CHARMM INterface and Graphics (CHARMMing) web user interface (http://www.charmming.org). Several lessons have already been developed with new ones easily added via a provided Python script. In addition to CHARMMing's new lessons functionality, web-based graphical capabilities have been overhauled and are fully compatible with modern mobile web browsers (e.g., phones and tablets), allowing easy integration of these advanced simulation techniques into coursework. Finally, one of the primary objections to web-based systems like CHARMMing has been that "point and click" simulation set-up does little to teach the user about the underlying physics, biology, and computational methods being applied. In response to this criticism, we have developed a freely available tutorial to bridge the gap between graphical simulation setup and the technical knowledge necessary to perform simulations without user interface assistance.
Atomic Charge Parameters for the Finite Difference Poisson-Boltzmann Method Using Electronegativity Neutralization.

PubMed

Yang, Qingyi; Sharp, Kim A

2006-07-01

An optimization of Rappe and Goddard's charge equilibration (QEq) method of assigning atomic partial charges is described. This optimization is designed for fast and accurate calculation of solvation free energies using the finite difference Poisson-Boltzmann (FDPB) method. The optimization is performed against experimental small molecule solvation free energies using the FDPB method and adjusting Rappe and Goddard's atomic electronegativity values. Using a test set of compounds for which experimental solvation energies are available and a rather small number of parameters, very good agreement was obtained with experiment, with a mean unsigned error of about 0.5 kcal/mol. The QEq atomic partial charge assignment method can reflect the effects of the conformational changes and solvent induction on charge distribution in molecules. In the second section of the paper we examined this feature with a study of the alanine dipeptide conformations in water solvent. The different contributions to the energy surface of the dipeptide were examined and compared with the results from fixed CHARMm charge potential, which is widely used for molecular dynamics studies.
Walter C. Williams with Brig. General Albert Boyd

NASA Technical Reports Server (NTRS)

1950-01-01

Walter C. Williams, (behind airplane model) Head of the National Advisory Committee for Aeronautics High-Speed Flight Research Station at Edwards Air Force Base in California is examining a Northrop X-4 research airplane with Brig. Gen. Albert Boyd, Commander of Edwards Air Force Base. At Edwards, the Air Force Air Material Command ran a brief program on the X-4 during the summer of 1950 before delivering it to the NACA. Data was collected on these 14 flights, so they were logged as NACA test flights. General Boyd made flight number 13. Air Force and NACA pilots completed a total of 82 flights on X-4 #2 (46-677) between August 1950 and September 1953. There are three things that made the Mojave Desert, where Edwards Air Force Base is located, so well suited for flight research. The first was the area's flying conditions--clear skies with great visibility almost every day of the year. The second was the 44-square-mile Rogers Dry Lake, a natural landing site that General Boyd referred to as 'God's gift to the Air Force.' The third was the unpopulated area surrounding the lakebed, which led to fewer complaints about aircraft noise (including sonic booms) than would have occurred in more populated areas. There was also less chance of injury to the surrounding population in the event of an aircraft accident.
15. "GENERAL, INSTRUMENTATION AND CONTROL SYSTEMS, ISOMETRIC." Test Area 1120. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

15. "GENERAL, INSTRUMENTATION AND CONTROL SYSTEMS, ISOMETRIC." Test Area 1-120. Specifications No. ENG04-353-55-72; Drawing No. 60-09-12; sheet 6 of 148; file no. 1320/57. Stamped: RECORD DRAWING - AS CONSTRUCTED. Below stamp: Contract no. 4338, no change. - Edwards Air Force Base, Air Force Rocket Propulsion Laboratory, Leuhman Ridge near Highways 58 & 395, Boron, Kern County, CA
Federal Personnel. Federal Agencies' Part-Time Employment Programs. Briefing Report to the Chairwoman, Task Force on Economic Security, Select Committee on Children, Youth and Families, House of Representatives.

ERIC Educational Resources Information Center

General Accounting Office, Washington, DC.

This report provides information on permanent part-time employment programs in the federal government. It contains statistical data showing general characteristics of the federal part-time work force and information about the part-time employment programs of the Office of Personnel Management (OPM), Veterans Administration, General Services…
49 CFR 236.10 - Electric locks, force drop type; where required.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Electric locks, force drop type; where required. 236.10 Section 236.10 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL... Rules and Instructions: All Systems General § 236.10 Electric locks, force drop type; where required...
48 CFR 237.109 - Services of quasi-military armed forces.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Services of quasi-military armed forces. 237.109 Section 237.109 Federal Acquisition Regulations System DEFENSE ACQUISITION... Contracts-General 237.109 Services of quasi-military armed forces. See 237.102-70b for prohibition on...
Simplified Relativistic Force Transformation Equation.

ERIC Educational Resources Information Center

Stewart, Benjamin U.

1979-01-01

A simplified relativistic force transformation equation is derived and then used to obtain the equation for the electromagnetic forces on a charged particle, calculate the electromagnetic fields due to a point charge with constant velocity, transform electromagnetic fields in general, derive the Biot-Savart law, and relate it to Coulomb's law.…
32 CFR 842.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Judge Advocate General, Headquarters, United States Air Force, Building 5683, Bolling AFB, DC 20332-6128. (g) HQ 9AF. Headquarters Ninth Air Force, Shaw AFB, SC 29152-5002. (h) Owner. A holder of a legal... for purposes of security are not owners. (i) HQ PACAF. Headquarters, Pacific Air Forces, Hickam AFB...
Mitigating the Cultural Challenges of SOF/Conventional Force Interdependence

DTIC Science & Technology

2013-03-01

Cultural Challenges of SOF / Conventional Force Interdependence 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...January 16, 2013. 31 Daniel French , “Integration of General Purpose Forces and Army Special Operations,” 1. 32 Edward L. Cardon , “Recognizing
Department of the Navy Justification of Estimates for Fiscal Year 1984 Submitted to Congress January 1983. Operation & Maintenance, Navy. Book 1. Budget Activity 1: Strategic Forces, Budget Activity 2: General Purpose Forces

DTIC Science & Technology

1983-01-01

Maintenance ............... 2-7-1 Budget Activity 8: Training , Medical and Other General Personnel Activities .......................... 3-8-1 Budget...1,152,156 Book 3 of 3 3. Intelligence and Communications 842,554 921,951 1,074,881 +152,930 8. Training , Medical, and Other General Personnel...2,533,174 2,625,858 2,607,008 Ship Maintenance & Modernization ... 3,812,413 4,365,516 4,391,134 Fleet Training
General stability of memory-type thermoelastic Timoshenko beam acting on shear force

NASA Astrophysics Data System (ADS)

Apalara, Tijani A.

2018-03-01

In this paper, we consider a linear thermoelastic Timoshenko system with memory effects where the thermoelastic coupling is acting on shear force under Neumann-Dirichlet-Dirichlet boundary conditions. The same system with fully Dirichlet boundary conditions was considered by Messaoudi and Fareh (Nonlinear Anal TMA 74(18):6895-6906, 2011, Acta Math Sci 33(1):23-40, 2013), but they obtained a general stability result which depends on the speeds of wave propagation. In our case, we obtained a general stability result irrespective of the wave speeds of the system.

Modeling and simulation of a Stewart platform type parallel structure robot

NASA Technical Reports Server (NTRS)

Lim, Gee Kwang; Freeman, Robert A.; Tesar, Delbert

1989-01-01

The kinematics and dynamics of a Stewart Platform type parallel structure robot (NASA's Dynamic Docking Test System) were modeled using the method of kinematic influence coefficients (KIC) and isomorphic transformations of system dependence from one set of generalized coordinates to another. By specifying the end-effector (platform) time trajectory, the required generalized input forces which would theoretically yield the desired motion were determined. It was found that the relationship between the platform motion and the actuators motion was nonlinear. In addition, the contribution to the total generalized forces, required at the actuators, from the acceleration related terms were found to be more significant than the velocity related terms. Hence, the curve representing the total required actuator force generally resembled the curve for the acceleration related force. Another observation revealed that the acceleration related effective inertia matrix I sub dd had the tendency to decouple, with the elements on the main diagonal of I sub dd being larger than the off-diagonal elements, while the velocity related inertia power array P sub ddd did not show such tendency. This tendency results in the acceleration related force curve of a given actuator resembling the acceleration profile of that particular actuator. Furthermore, it was indicated that the effective inertia matrix for the legs is more decoupled than that for the platform. These observations provide essential information for further research to develop an effective control strategy for real-time control of the Dynamic Docking Test System.
Radiative Forcing by Well-Mixed Greenhouse Gases: Estimates from Climate Models in the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4)

NASA Technical Reports Server (NTRS)

Collins, W. D.; Ramaswamy, V.; Schwarzkopf, M. D.; Sun, Y.; Portmann, R. W.; Fu, Q.; Casanova, S. E. B.; Dufresne, J.-L.; Fillmore, D. W.; Forster, P. M. D.;

2006-01-01

The radiative effects from increased concentrations of well-mixed greenhouse gases (WMGHGs) represent the most significant and best understood anthropogenic forcing of the climate system. The most comprehensive tools for simulating past and future climates influenced by WMGHGs are fully coupled atmosphere-ocean general circulation models (AOGCMs). Because of the importance of WMGHGs as forcing agents it is essential that AOGCMs compute the radiative forcing by these gases as accurately as possible. We present the results of a radiative transfer model intercomparison between the forcings computed by the radiative parameterizations of AOGCMs and by benchmark line-by-line (LBL) codes. The comparison is focused on forcing by CO2, CH4, N2O, CFC-11, CFC-12, and the increased H2O expected in warmer climates. The models included in the intercomparison include several LBL codes and most of the global models submitted to the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4). In general, the LBL models are in excellent agreement with each other. However, in many cases, there are substantial discrepancies among the AOGCMs and between the AOGCMs and LBL codes. In some cases this is because the AOGCMs neglect particular absorbers, in particular the near-infrared effects of CH4 and N2O, while in others it is due to the methods for modeling the radiative processes. The biases in the AOGCM forcings are generally largest at the surface level. We quantify these differences and discuss the implications for interpreting variations in forcing and response across the multimodel ensemble of AOGCM simulations assembled for the IPCC AR4.

48 CFR 970.2270 - Unemployment compensation.

Code of Federal Regulations, 2010 CFR

2010-10-01

... the negotiation and administration of cost-reimbursement type contracts, that economical and practical... work force stability and the general outlook with respect to future work force stability; (v) In a...
Roll Damping Derivatives from Generalized Lifting-Surface Theory and Wind Tunnel Forced-Oscillation Tests

NASA Technical Reports Server (NTRS)

Pototzky, Anthony S; Murphy, Patrick C.

2014-01-01

Improving aerodynamic models for adverse loss-of-control conditions in flight is an area being researched under the NASA Aviation Safety Program. Aerodynamic models appropriate for loss of control conditions require a more general mathematical representation to predict nonlinear unsteady behaviors. As more general aerodynamic models are studied that include nonlinear higher order effects, the possibility of measurements that confound aerodynamic and structural responses are probable. In this study an initial step is taken to look at including structural flexibility in analysis of rigid-body forced-oscillation testing that accounts for dynamic rig, sting and balance flexibility. Because of the significant testing required and associated costs in a general study, it makes sense to capitalize on low cost analytical methods where possible, especially where structural flexibility can be accounted for by a low cost method. This paper provides an initial look at using linear lifting surface theory applied to rigid-body aircraft roll forced-oscillation tests.
Neutron star mergers as a probe of modifications of general relativity with finite-range scalar forces

NASA Astrophysics Data System (ADS)

Sagunski, Laura; Zhang, Jun; Johnson, Matthew C.; Lehner, Luis; Sakellariadou, Mairi; Liebling, Steven L.; Palenzuela, Carlos; Neilsen, David

2018-03-01

Observations of gravitational radiation from compact binary systems provide an unprecedented opportunity to test general relativity in the strong field dynamical regime. In this paper, we investigate how future observations of gravitational radiation from binary neutron star mergers might provide constraints on finite-range forces from a universally coupled massive scalar field. Such scalar degrees of freedom (d.o.f.) are a characteristic feature of many extensions of general relativity. For concreteness, we work in the context of metric f (R ) gravity, which is equivalent to general relativity and a universally coupled scalar field with a nonlinear potential whose form is fixed by the choice of f (R ). In theories where neutron stars (or other compact objects) obtain a significant scalar charge, the resulting attractive finite-range scalar force has implications for both the inspiral and merger phases of binary systems. We first present an analysis of the inspiral dynamics in Newtonian limit, and forecast the constraints on the mass of the scalar and charge of the compact objects for the Advanced LIGO gravitational wave observatory. We then perform a comparative study of binary neutron star mergers in general relativity with those of a one-parameter model of f (R ) gravity using fully relativistic hydrodynamical simulations. These simulations elucidate the effects of the scalar on the merger and postmerger dynamics. We comment on the utility of the full waveform (inspiral, merger, postmerger) to probe different regions of parameter space for both the particular model of f (R ) gravity studied here and for finite-range scalar forces more generally.
Special Operations Forces of Hungary: Is a Transformation Necessary?

DTIC Science & Technology

2010-12-01

inflatable Zodiac boats. With this, the battalion is capable to infiltrate two platoons at the same time through using water ways, and the battalion is...SPECIAL OPERATIONS FORCES OF HUNGARY: IS A TRANSFORMATION NECESSARY? A thesis presented to the Faculty of the U.S. Army Command and...General Staff College in partial fulfillment of the requirements for the degree MASTER OF MILITARY ART AND SCIENCE General Studies by
Urban Counterinsurgency: Case Studies and Implications for U.S. Military Forces

DTIC Science & Technology

1989-10-01

Politica Electoral Independiente (Original name for Christian Socialist Party)--Venezuela CRS Compagnies Republicaines de Securite (Republican Security...arguably has had the greatest political and military impact of any of the colonial insurgencies in the post -World War II period. The lessons drawn from...Def. SDECE Governor Cmdg General Post General 10th Mil. Region No. Af. Liai- National Territorial Gendar- Armed Forces son Services Police Police
Muscle fatigue: general understanding and treatment

PubMed Central

Wan, Jing-jing; Qin, Zhen; Wang, Peng-yuan; Sun, Yang; Liu, Xia

2017-01-01

Muscle fatigue is a common complaint in clinical practice. In humans, muscle fatigue can be defined as exercise-induced decrease in the ability to produce force. Here, to provide a general understanding and describe potential therapies for muscle fatigue, we summarize studies on muscle fatigue, including topics such as the sequence of events observed during force production, in vivo fatigue-site evaluation techniques, diagnostic markers and non-specific but effective treatments. PMID:28983090
The Lavelle Affair: An Air Force Case Study in Ethics

DTIC Science & Technology

2016-06-01

THE LAVELLE AFFAIR: AN AIR FORCE CASE STUDY IN ETHICS BY KRISTINA ELLIS A THESIS PRESENTED TO THE FACULTY OF THE SCHOOL OF... ethical transgressions. As such, the story of General Lavelle’s wartime command experiences became a case study in ethics and integrity within Air...1 1 THE LIFE AND CAREER OF GENERAL LAVELLE 8 1 VIETNAM 14 2 CIVIL-MILITARY RELATIONS 25 2 ETHICAL
Conflict and Consensus in the Soviet Armed Forces

DTIC Science & Technology

1989-10-01

later example of the phenomenon was the appointment of Colonel General Mikhail A. Moiseyev to replace Marshal Akhromeyev as chief of the General Staff...political environment of the Strategic Rocket Forces, however, changed markedly after Mikhail Gorbachev came to power in March 1985. In January 1986...V"yunenko, B. N. Makeyev , V. D. Skugarev, Admiral S. Q. Gorshkov, ed., Voyvnno.morskoy Flat: rol’, Perspektiuy razuitiya, ispol’zovaniye, Voyenizdat
Motion and force control of multiple robotic manipulators

NASA Technical Reports Server (NTRS)

Wen, John T.; Kreutz-Delgado, Kenneth

1992-01-01

This paper addresses the motion and force control problem of multiple robot arms manipulating a cooperatively held object. A general control paradigm is introduced which decouples the motion and force control problems. For motion control, different control strategies are constructed based on the variables used as the control input in the controller design. There are three natural choices; acceleration of a generalized coordinate, arm tip force vectors, and the joint torques. The first two choices require full model information but produce simple models for the control design problem. The last choice results in a class of relatively model independent control laws by exploiting the Hamiltonian structure of the open loop system. The motion control only determines the joint torque to within a manifold, due to the multiple-arm kinematic constraint. To resolve the nonuniqueness of the joint torques, two methods are introduced. If the arm and object models are available, an optimization can be performed to best allocate the desired and effector control force to the joint actuators. The other possibility is to control the internal force about some set point. It is shown that effective force regulation can be achieved even if little model information is available.
THROW AWAY THE BOX: RETHINKING LOGISTICS INTEGRATION BETWEEN SPECIAL OPERATIONS AND GENERAL PURPOSE FORCES

DTIC Science & Technology

2015-02-13

Ft Carson CO; Logistics Officer, 10th Special Forces Group ( SFG ) Airborne (A) and Combined Joint Special Operations Task Force (CJSOTF) Arabian...ENDURING FREEDOM; Commander 7th SFG (A) Group Support Battalion, Eglin AFB, FL for two years and deployed to Afghanistan twice serving as the
TASK FORCE REPORT ON ASSESSMENT AND EVALUATION.

ERIC Educational Resources Information Center

MORRIS, ROBERT

THE TASK FORCE ON ASSESSMENT AND EVALUATION HAS BEEN CHARGED TO RECOMMEND THE MOST EFFECTIVE MEANS FOR ASSESSING AND EVALUATING THE SHORT-TERM ACTIVITIES AND THE LONG-TERM ACHIEVEMENTS OF ACTION FOR BOSTON COMMUNITY DEVELOPMENT. THE GENERAL OBJECTIVES OF THE TASK FORCE ARE--THE ANALYSIS OF DATA RELEVANT FOR EVALUATING DAY-BY-DAY DECISION-MAKING,…
10 CFR 1049.8 - Training of SPR Protective Force Officers and qualification to carry firearms.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false Training of SPR Protective Force Officers and qualification to carry firearms. 1049.8 Section 1049.8 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) LIMITED... Force Officers shall successfully complete training required by applicable Department of Energy orders...
Reduction in Force: The Legal Aspects.

ERIC Educational Resources Information Center

Ware, Martha L.

Six legal issues surrounding a school district's reduction in force are described in this twelfth chapter in a book on school law. First, the courts generally hold that the school board must prove that a reduction in force (RIF) is inescapable. The second issue revolves around which positions and employees are being eliminated. In deciding such…
Possible Potentials Responsible for Stable Circular Relativistic Orbits

ERIC Educational Resources Information Center

Kumar, Prashant; Bhattacharya, Kaushik

2011-01-01

Bertrand's theorem in classical mechanics of the central force fields attracts us because of its predictive power. It categorically proves that there can only be two types of forces which can produce stable, circular orbits. In this paper an attempt has been made to generalize Bertrand's theorem to the central force problem of relativistic…
An analysis of the high-latitude thermospheric wind pattern calculated by a thermospheric general circulation model. I - Momentum forcing

NASA Technical Reports Server (NTRS)

Killeen, T. L.; Roble, R. G.

1984-01-01

A diagnostic processor (DP) was developed for analysis of hydrodynamic and thermodynamic processes predicted by the NCAR thermospheric general circulation model (TGCM). The TGCM contains a history file on the projected wind, temperature and composition fields at each grid point for each hour of universal time. The DP assimilates the history file plus ion drag tensors and drift velocities, specific heats, coefficients of viscosity, and thermal conductivity and calculates the individual forcing terms for the momentum and energy equations for a given altitude. Sample momentum forcings were calculated for high latitudes in the presence of forcing by solar radiation and magnetospheric convection with a 60 kV cross-tail potential, i.e., conditions on Oct. 21, 1981. It was found that ion drag and pressure forces balance out at F region heights where ion drift velocities are small. The magnetic polar cap/auroral zone boundary featured the largest residual force or net acceleration. Diurnal oscillations were detected in the thermospheric convection, and geostrophic balance was dominant in the E layer.
Out-of-plane aerodynamic forces on slender ogive-nosed cylinders

NASA Astrophysics Data System (ADS)

Lacey, M. R.

An ogive-nosed cylinder with a nose fineness of 3 and a body length equal to 12 diameters, has been tested at a constant crossflow Reynolds' number of 85000 and constant crossflow Mach number of 0.1 in the angle of incidence range 0° - 90°, A method of force measurement has been devised to determine the magnitude of the aerodynamic forces on the ogive cylinder and a statistical analysis was developed to predict its accuracy for any model configuration. It was found generally that the results of static loading tests lay well within the stipulated accuracy limits. The out-of-plane forest and moments measured generally agreed well with published data and predictions based on experimental results. Similar agreement was obtained for in-plane forces and moments. The results for the effect of model roll-orientation on the out-of-plane force indicated the existence of two distinct states of asymmetry in the wake, with an absence of any intermediate states. The out-of-plane forces showed no correlation with the position of model nose imperfections, supporting the findings of previous experimenters. Reducing the length of the cylindrical body section of the model served first to reduce the out-of-plane force but subsequently produced a recovery in its magnitude with further shortening. These results agreed well with the prediction method selected. Increased free stream turbulence tended to have less effect on the distribution of the out-of-plane force than previously reported; no flow unsteadiness was observed and no change in direction of roce was recorded. Increased nose tip radius generally reduced the out- of plane force and considerable directional instability was observed. This reduction was, however, not true for all incidence angles. The directional instability was due probably to the removal of the nose tip imperfections, resulting in an inability of the wake to establish a preferred direction of asymmetry throughout the range of incidence.
A randomized comparison of intraoperative PerfecTemp and forced-air warming during open abdominal surgery.

PubMed

Egan, Cameron; Bernstein, Ethan; Reddy, Desigen; Ali, Madi; Paul, James; Yang, Dongsheng; Sessler, Daniel I

2011-11-01

The PerfecTemp is an underbody resistive warming system that combines servocontrolled underbody warming with viscoelastic foam pressure relief. Clinical efficacy of the system has yet to be formally evaluated. We therefore tested the hypothesis that intraoperative distal esophageal (core) temperatures with the PerfecTemp (underbody resistive) warming system are noninferior to upper-body forced-air warming in patients undergoing major open abdominal surgery under general anesthesia. Adults scheduled for elective major open abdominal surgery (liver, pancreas, gynecological, and colorectal surgery) under general anesthesia were enrolled at 2 centers. Patients were randomly assigned to underbody resistive or forced-air warming. Resistive heating started when patients were transferred to the operating room table; forced-air warming started after patients were draped. The primary outcome was noninferiority of intraoperative time-weighted average core temperature, adjusted for baseline characteristics and using a buffer of 0.5°C. Thirty-six patients were randomly assigned to underbody resistive heating and 34 to forced-air warming. Baseline and surgical characteristics were generally similar. We had sufficient evidence (P=0.018) to conclude that underbody resistive warming is not worse than (i.e., noninferior to) upper-body forced-air warming in the time-weighted average intraoperative temperature, with a mean difference of -0.12°C [95% confidence interval (CI) -0.37 to 0.14]. Core temperatures at the end of surgery averaged 36.3°C [95% CI 36 to 36.5] in the resistive warming patients and 36.6°C [95% CI 36.4 to 36.8] in those assigned to forced-air warming for a mean difference of -0.34°C [95% CI -0.69 to 0.01]. Mean intraoperative time-weighted average core temperatures were no different, and significantly noninferior, with underbody resistive heating in comparison with upper-body forced-air warming. Underbody resistive heating may be an alternative to forced-air warming.
The role of response force on the persistence and structure of behavior during extinction.

PubMed

Pinkston, Jonathan W; Foss, Erica K

2018-01-01

Behavior Momentum Theory has emerged as a prominent account of resistance to change in both basic and applied research. Although laboratory studies often define precise, repeatable responses, application research often deals with response classes that may vary widely along a number of dimensions. In general, Behavior Momentum Theory has not addressed how response dimensions impact resistance to change, providing an opportunity to expand the model in new directions. Four rats pressed a force transducer under a multiple variable interval (VI) 60-s VI 60-s schedule of reinforcement. In one component, responses satisfied the schedule only if the response force fell within a "low" force band requirement; responses in the other schedule were required to satisfy a "high" force band. Once responding stabilized, extinction was programmed for three sessions. Then, the procedures were replicated. The results showed that response force came under discriminative control, but force requirements had no impact on resistance to extinction. In a follow-up condition, the schedule was changed to a multiple VI 30-s VI 120-s schedule and the low-force band operated in both components. The results showed that behavior maintained by the VI 30-s schedule was generally more resistant to extinction. A secondary analysis showed that force distributions created under baseline maintained during extinction. Overall, the results suggest that differential response force requirements prevailing in steady state do not affect the course of extinction. © 2018 Society for the Experimental Analysis of Behavior.

Correlates of Forced Sex Among Populations of Men Who Have Sex with Men in Thailand

PubMed Central

Guadamuz, Thomas E.; Wimonsate, Wipas; Varangrat, Anchalee; Phanuphak, Praphan; Jommaroeng, Rapeepun; Mock, Philip A.; Tappero, Jordan W.

2011-01-01

Although forced sex is a correlate of HIV infection, its prevalence and associated risks are not well described among men who have sex with men (MSM) in developing-country settings. Between March and October 2005, we assessed the prevalence of forced sex and correlates among populations of MSM (this includes general MSM, male sex workers, and male-to-female transgender persons) in Thailand using a community-based sample. Participants were enrolled from venues around Bangkok, Chiangmai, and Phuket using venue day-time sampling. Handheld computer-assisted self-interviewing was used to collect demographic and behavioral data and logistic regression evaluated factors associated with forced sex, defined as ever being forced to have sexual intercourse against one’s will. Of the 2,049 participants (M age, 24.8 years), a history of forced sex was reported by 376 (18.4%) men and, of these, most were forced by someone they knew (83.8%), forced more than once (67.3%), and had first occurrence during adolescence (55.1%). In multivariate analysis, having a history of forced sex was significantly associated with being recruited in Phuket, classification as general MSM or transgender (versus classification as male sex worker), drug use, increased number of male sexual partners, and buying sex. The findings in our assessment were consistent with assessments from Western countries. Longitudinal studies are needed to understand the mechanisms of the relationships between forced sex correlates found in our assessment and HIV acquisition and transmission risks. PMID:19830540
Correlates of forced sex among populations of men who have sex with men in Thailand.

PubMed

Guadamuz, Thomas E; Wimonsate, Wipas; Varangrat, Anchalee; Phanuphak, Praphan; Jommaroeng, Rapeepun; Mock, Philip A; Tappero, Jordan W; van Griensven, Frits

2011-04-01

Although forced sex is a correlate of HIV infection, its prevalence and associated risks are not well described among men who have sex with men (MSM) in developing-country settings. Between March and October 2005, we assessed the prevalence of forced sex and correlates among populations of MSM (this includes general MSM, male sex workers, and male-to-female transgender persons) in Thailand using a community-based sample. Participants were enrolled from venues around Bangkok, Chiangmai, and Phuket using venue day-time sampling. Handheld computer-assisted self-interviewing was used to collect demographic and behavioral data and logistic regression evaluated factors associated with forced sex, defined as ever being forced to have sexual intercourse against one's will. Of the 2,049 participants (M age, 24.8 years), a history of forced sex was reported by 376 (18.4%) men and, of these, most were forced by someone they knew (83.8%), forced more than once (67.3%), and had first occurrence during adolescence (55.1%). In multivariate analysis, having a history of forced sex was significantly associated with being recruited in Phuket, classification as general MSM or transgender (versus classification as male sex worker), drug use, increased number of male sexual partners, and buying sex. The findings in our assessment were consistent with assessments from Western countries. Longitudinal studies are needed to understand the mechanisms of the relationships between forced sex correlates found in our assessment and HIV acquisition and transmission risks.
Oscillation theorems for second order nonlinear forced differential equations.

PubMed

Salhin, Ambarka A; Din, Ummul Khair Salma; Ahmad, Rokiah Rozita; Noorani, Mohd Salmi Md

2014-01-01

In this paper, a class of second order forced nonlinear differential equation is considered and several new oscillation theorems are obtained. Our results generalize and improve those known ones in the literature.
Inspector General Complaints

Science.gov Websites

Speeches Archive Former AF Top 3 Viewpoints and Speeches Air Force Warrior Games 2017 Events 2018 Air Force Strategic Documents Desert Storm 25th Anniversary Observances DoD Warrior Games Portraits in Courage
Towards understanding what contributes to forming an opinion

NASA Astrophysics Data System (ADS)

Wang, Peng; Song, Jia; Huo, Jie; Hao, Rui; Wang, Xu-Ming

Opinion evolution mechanism can be captured by physical modeling. In this paper, a kinetic equation is established by defining a generalized displacement(cognitive level), a driving force and the related factors such as generalized potential, information quantity and attitude. It has been shown that the details of opinion evolution depend on the type of the driving force, self-dominated driving or environment-dominated driving. In the former case, the participants can have their attitudes changed in the process of competition between the self-driving force and environment-driving force. In the latter case, all of the participants are pulled by the environment. Some regularities behind the dynamics of opinion are also revealed, for instance, the information entropy decays with time in a special way, etc. The results may help us to get some deep understanding for the formation of a public opinion.
Self-propelled Brownian spinning top: dynamics of a biaxial swimmer at low Reynolds numbers.

PubMed

Wittkowski, Raphael; Löwen, Hartmut

2012-02-01

Recently the Brownian dynamics of self-propelled (active) rodlike particles was explored to model the motion of colloidal microswimmers, catalytically driven nanorods, and bacteria. Here we generalize this description to biaxial particles with arbitrary shape and derive the corresponding Langevin equation for a self-propelled Brownian spinning top. The biaxial swimmer is exposed to a hydrodynamic Stokes friction force at low Reynolds numbers, to fluctuating random forces and torques as well as to an external and an internal (effective) force and torque. The latter quantities control its self-propulsion. Due to biaxiality and hydrodynamic translational-rotational coupling, the Langevin equation can only be solved numerically. In the special case of an orthotropic particle in the absence of external forces and torques, the noise-free (zero-temperature) trajectory is analytically found to be a circular helix. This trajectory is confirmed numerically to be more complex in the general case of an arbitrarily shaped particle under the influence of arbitrary forces and torques involving a transient irregular motion before ending up in a simple periodic motion. By contrast, if the external force vanishes, no transient regime is found, and the particle moves on a superhelical trajectory. For orthotropic particles, the noise-averaged trajectory is a generalized concho-spiral. We furthermore study the reduction of the model to two spatial dimensions and classify the noise-free trajectories completely finding circles, straight lines with and without transients, as well as cycloids and arbitrary periodic trajectories. © 2012 American Physical Society
Balance decrements are associated with age-related muscle property changes.

PubMed

Hasson, Christopher J; van Emmerik, Richard E A; Caldwell, Graham E

2014-08-01

In this study, a comprehensive evaluation of static and dynamic balance abilities was performed in young and older adults and regression analysis was used to test whether age-related variations in individual ankle muscle mechanical properties could explain differences in balance performance. The mechanical properties included estimates of the maximal isometric force capability, force-length, force-velocity, and series elastic properties of the dorsiflexors and individual plantarflexor muscles (gastrocnemius and soleus). As expected, the older adults performed more poorly on most balance tasks. Muscular maximal isometric force, optimal fiber length, tendon slack length, and velocity-dependent force capabilities accounted for up to 60% of the age-related variation in performance on the static and dynamic balance tests. In general, the plantarflexors had a stronger predictive role than the dorsiflexors. Plantarflexor stiffness was strongly related to general balance performance, particularly in quiet stance; but this effect did not depend on age. Together, these results suggest that age-related differences in balance performance are explained in part by alterations in muscular mechanical properties.
Effect of the Magnus force on skyrmion relaxation dynamics

NASA Astrophysics Data System (ADS)

Brown, Barton L.; Täuber, Uwe C.; Pleimling, Michel

2018-01-01

We perform systematic Langevin molecular dynamics simulations of interacting skyrmions in thin films. The interplay between the Magnus force, the repulsive skyrmion-skyrmion interaction, and the thermal noise yields different regimes during nonequilibrium relaxation. In the noise-dominated regime, the Magnus force enhances the disordering effects of the thermal noise. In the Magnus-force-dominated regime, the Magnus force cooperates with the skyrmion-skyrmion interaction to yield a dynamic regime with slow decaying correlations. These two regimes are characterized by different values of the aging exponent. In general, the Magnus force accelerates the approach to the steady state.
Multiple-state quantum Otto engine, 1D box system

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

Latifah, E., E-mail: enylatifah@um.ac.id; Purwanto, A.

2014-03-24

Quantum heat engines produce work using quantum matter as their working substance. We studied adiabatic and isochoric processes and defined the general force according to quantum system. The processes and general force are used to evaluate a quantum Otto engine based on multiple-state of one dimensional box system and calculate the efficiency. As a result, the efficiency depends on the ratio of initial and final width of system under adiabatic processes.
Investigation in Construction Entrepreneurship.

DTIC Science & Technology

1980-05-01

7 -ABG 559 AIR FORCE INST OF TECH WRIGHT-PATTERSON AFB OH F/G 5/3 INVESTIGATION IN CONSTRUCTION ENTREPRENEURSHIP . (U)IKAY 80 F EP 6ULD UNCLASSIFIED...CONSTRUCTION ENTREPRENEURSHIP by Accession For FREDERICK ELLIOTT GOULD NTIS OiYA&I DC TAB B.S., U.S. Air Force Academy Uneuc d (1977) Justification By_...Included is a study of general entrepreneurship , a discussion of the characteristics of the construction industry which differentiates it from a general
Gravitational body forces focus North American intraplate earthquakes

USGS Publications Warehouse

Levandowski, William Brower; Zellman, Mark; Briggs, Richard

2017-01-01

Earthquakes far from tectonic plate boundaries generally exploit ancient faults, but not all intraplate faults are equally active. The North American Great Plains exemplify such intraplate earthquake localization, with both natural and induced seismicity generally clustered in discrete zones. Here we use seismic velocity, gravity and topography to generate a 3D lithospheric density model of the region; subsequent finite-element modelling shows that seismicity focuses in regions of high-gravity-derived deviatoric stress. Furthermore, predicted principal stress directions generally align with those observed independently in earthquake moment tensors and borehole breakouts. Body forces therefore appear to control the state of stress and thus the location and style of intraplate earthquakes in the central United States with no influence from mantle convection or crustal weakness necessary. These results show that mapping where gravitational body forces encourage seismicity is crucial to understanding and appraising intraplate seismic hazard.
The role of earth radiation budget studies in climate and general circulation research

NASA Technical Reports Server (NTRS)

Ramanathan, V.

1987-01-01

The use of earth radiation budget (ERB) data for climate and general circulation research is studied. ERB measurements obtained in the 1960's and 1970's have provided data on planetary brightness, planetary global energy balances, the greenhouse effect, solar insolation, meridional heat transport by oceans and atmospheres, regional forcing, climate feedback processes, and the computation of albedo values in low latitudes. The role of clouds in governing climate, in influencing the general circulation, and in determining the sensitivity of climate to external perturbations needs to be researched; a procedure for analyzing the ERB data, which will address these problems, is described. The approach involves estimating the clear-sky fluxes from the high spatial resolution scanner measurement and defining a cloud radiative forcing; the global average of the sum of the solar and long-wave cloud forcing yields the net radiative effect of clouds on the climate.
Gravitational body forces focus North American intraplate earthquakes

PubMed Central

Levandowski, Will; Zellman, Mark; Briggs, Rich

2017-01-01

Earthquakes far from tectonic plate boundaries generally exploit ancient faults, but not all intraplate faults are equally active. The North American Great Plains exemplify such intraplate earthquake localization, with both natural and induced seismicity generally clustered in discrete zones. Here we use seismic velocity, gravity and topography to generate a 3D lithospheric density model of the region; subsequent finite-element modelling shows that seismicity focuses in regions of high-gravity-derived deviatoric stress. Furthermore, predicted principal stress directions generally align with those observed independently in earthquake moment tensors and borehole breakouts. Body forces therefore appear to control the state of stress and thus the location and style of intraplate earthquakes in the central United States with no influence from mantle convection or crustal weakness necessary. These results show that mapping where gravitational body forces encourage seismicity is crucial to understanding and appraising intraplate seismic hazard. PMID:28211459
Identification of internal properties of fibres and micro-swimmers

NASA Astrophysics Data System (ADS)

Plouraboué, Franck; Thiam, E. Ibrahima; Delmotte, Blaise; Climent, Eric

2017-01-01

In this paper, we address the identifiability of constitutive parameters of passive or active micro-swimmers. We first present a general framework for describing fibres or micro-swimmers using a bead-model description. Using a kinematic constraint formulation to describe fibres, flagellum or cilia, we find explicit linear relationship between elastic constitutive parameters and generalized velocities from computing contact forces. This linear formulation then permits one to address explicitly identifiability conditions and solve for parameter identification. We show that both active forcing and passive parameters are both identifiable independently but not simultaneously. We also provide unbiased estimators for generalized elastic parameters in the presence of Langevin-like forcing with Gaussian noise using a Bayesian approach. These theoretical results are illustrated in various configurations showing the efficiency of the proposed approach for direct parameter identification. The convergence of the proposed estimators is successfully tested numerically.
32 CFR 855.1 - Policy.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 6 2010-07-01 2010-07-01 false Policy. 855.1 Section 855.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE AIRCRAFT CIVIL AIRCRAFT USE OF UNITED STATES AIR FORCE AIRFIELDS General Provisions § 855.1 Policy. The Air Force establishes and uses its airfields to support the scope and level of...
12 CFR 339.7 - Forced placement of flood insurance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Forced placement of flood insurance. 339.7... GENERAL POLICY LOANS IN AREAS HAVING SPECIAL FLOOD HAZARDS § 339.7 Forced placement of flood insurance. If... not covered by flood insurance or is covered by flood insurance in an amount less than the amount...
Examining the Impact of External Influences on Police Use of Deadly Force over Time.

ERIC Educational Resources Information Center

White, Michael D.

2002-01-01

Used interrupted time-series analysis (ARIMA) to study the impact of legislation and judicial intervention on the use of deadly force by police officers in Philadelphia, Pennsylvania. Findings generally suggest that dynamic changes in the internal working environment can outweigh the influence of external mechanisms on deadly force use. Findings…
Non-Uniqueness of the Point of Application of the Buoyancy Force

ERIC Educational Resources Information Center

Kliava, Janis; Megel, Jacques

2010-01-01

Even though the buoyancy force (also known as the Archimedes force) has always been an important topic of academic studies in physics, its point of application has not been explicitly identified yet. We present a quantitative approach to this problem based on the concept of the hydrostatic energy, considered here for a general shape of the…
22 CFR 71.2 - Requests for naval force in foreign port.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Requests for naval force in foreign port. 71.2... ESTATES PROTECTION AND WELFARE OF CITIZENS AND THEIR PROPERTY General Activities § 71.2 Requests for naval... of a naval force in a foreign port unless a public emergency so necessitates. The request may be...
47 CFR 80.141 - General provisions for ship stations.

Code of Federal Regulations, 2013 CFR

2013-10-01

... storm, subfreezing air temperatures associated with gale force winds causing severe icing on superstructures, or winds of force 10 or above on the Beaufort scale for which no storm warning has been received...

47 CFR 80.141 - General provisions for ship stations.

Code of Federal Regulations, 2012 CFR

2012-10-01

... storm, subfreezing air temperatures associated with gale force winds causing severe icing on superstructures, or winds of force 10 or above on the Beaufort scale for which no storm warning has been received...
47 CFR 80.141 - General provisions for ship stations.

Code of Federal Regulations, 2011 CFR

2011-10-01

... storm, subfreezing air temperatures associated with gale force winds causing severe icing on superstructures, or winds of force 10 or above on the Beaufort scale for which no storm warning has been received...
47 CFR 80.141 - General provisions for ship stations.

Code of Federal Regulations, 2014 CFR

2014-10-01

... storm, subfreezing air temperatures associated with gale force winds causing severe icing on superstructures, or winds of force 10 or above on the Beaufort scale for which no storm warning has been received...
47 CFR 80.141 - General provisions for ship stations.

Code of Federal Regulations, 2010 CFR

2010-10-01

... storm, subfreezing air temperatures associated with gale force winds causing severe icing on superstructures, or winds of force 10 or above on the Beaufort scale for which no storm warning has been received...
ECN-3931

NASA Image and Video Library

1974-01-28

This photograph shows a modified General Dynamics TACT/F-111A Aardvaark with supercritical wings installed. The aircraft, with flaps and landing gear down, is in a decending turn over Rogers Dry Lakebed at Edwards Air Force Base. Starting in 1971 the NASA Flight Research Center and the Air Force undertook a major research and flight testing program, using F-111A (#63-9778), which would span almost 20 years before completion. Intense interest over the results coming from the NASA F-8 supercritical wing program spurred NASA and the Air Force to modify the General Dynamics-Convair F-111A to explore the application of supercritical wing technology to maneuverable military aircraft. This flight program was called Transonic Aircraft Technology (TACT).
Nonlinear coupled equations for electrochemical cells as developed by the general equation for nonequilibrium reversible-irreversible coupling.

PubMed

Bedeaux, Dick; Kjelstrup, Signe; Öttinger, Hans Christian

2014-09-28

We show how the Butler-Volmer and Nernst equations, as well as Peltier effects, are contained in the general equation for nonequilibrium reversible and irreversible coupling, GENERIC, with a unique definition of the overpotential. Linear flux-force relations are used to describe the transport in the homogeneous parts of the electrochemical system. For the electrode interface, we choose nonlinear flux-force relationships. We give the general thermodynamic basis for an example cell with oxygen electrodes and electrolyte from the solid oxide fuel cell. In the example cell, there are two activated chemical steps coupled also to thermal driving forces at the surface. The equilibrium exchange current density obtains contributions from both rate-limiting steps. The measured overpotential is identified at constant temperature and stationary states, in terms of the difference in electrochemical potential of products and reactants. Away from these conditions, new terms appear. The accompanying energy flux out of the surface, as well as the heat generation at the surface are formulated, adding to the general thermodynamic basis.
Nonlinear coupled equations for electrochemical cells as developed by the general equation for nonequilibrium reversible-irreversible coupling

NASA Astrophysics Data System (ADS)

Bedeaux, Dick; Kjelstrup, Signe; Öttinger, Hans Christian

2014-09-01

We show how the Butler-Volmer and Nernst equations, as well as Peltier effects, are contained in the general equation for nonequilibrium reversible and irreversible coupling, GENERIC, with a unique definition of the overpotential. Linear flux-force relations are used to describe the transport in the homogeneous parts of the electrochemical system. For the electrode interface, we choose nonlinear flux-force relationships. We give the general thermodynamic basis for an example cell with oxygen electrodes and electrolyte from the solid oxide fuel cell. In the example cell, there are two activated chemical steps coupled also to thermal driving forces at the surface. The equilibrium exchange current density obtains contributions from both rate-limiting steps. The measured overpotential is identified at constant temperature and stationary states, in terms of the difference in electrochemical potential of products and reactants. Away from these conditions, new terms appear. The accompanying energy flux out of the surface, as well as the heat generation at the surface are formulated, adding to the general thermodynamic basis.
Radiation Force Caused by Scattering, Absorption, and Emission of Light by Nonspherical Particles

NASA Technical Reports Server (NTRS)

Mishchenko, Michael I.; Hansen, James E. (Technical Monitor)

2001-01-01

General formulas for computing the radiation force exerted on arbitrarily oriented and arbitrarily shaped nonspherical particles due to scattering, absorption, and emission of electromagnetic radiation are derived. For randomly oriented particles with a plane of symmetry, the formula for the average radiation force caused by the particle response to external illumination reduces to the standard Debye formula derived from the Lorenz-Mie theory, whereas the average radiation force caused by emission vanishes.
Army Family Policies and Practices: A Summary of Regulations, Letters, Pamphlets, and Circulars That Impact on Army Families

DTIC Science & Technology

1990-05-01

AR 60-10 Army and Air Force Exchange Service (AAFES) General Policies.. ................. . . . 12 AR 60-2 0 Army and Air Force Exchange Service (AAFES...Initial Active Duty, Initial Active Duty for Training, and Reserve Forces Duty . . . . . . ........... 29 AR 601-27 Military Entrance Processing...AR 608-20 Voting by Personnel of the Armed Forces . . . . .... 35 AR 608-25 Retirement Services Program . ...... 36 AR 608-61 Application for
Developing Senior Navy Leaders: Requirements for Flag Officer Expertise Today and in the Future

DTIC Science & Technology

2008-01-01

who reach flag ranks have already passed numerous tests of their leadership skills, so there is little differentiation in either the demand for or...NooN) Master Chief Petty Officer (MCPON) Director of Test and Evaluation Technology Requirements (N091) Surgeon General of the Navy (N093) Chief of Navy...Operations Fleet Forces Command Naval Reserve Forces Operational Test and Evaluation Forces Naval Special Warfare Command U.S. Naval Forces Central Command
Epidemoligic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides: Baseline Questionnaires

DTIC Science & Technology

1982-11-01

19M I Prepared for: The Surgeon General ~, United States Air Force Washington, D.C. 20314 USAF SCHOOL OF AEROSPACE MEDICINE Brooks Air Force Base...School of Aerospace Medicine , Aerospace Medical Division, AFSC, Brooks Air Force Base, Texas, under job order 2767-00-01. la When Government drawings...Wolfe. Ljeujenant; Colonel, USAF. M C S F. IlFONMING ORGANIZATION NAMS AND AODRESS 10. PROGRAM ELEMENT. PROJECT, TASKUSAF School of Aerospace Medicine
The Civil-Military Gap in the United States. Does It Exist, Why, and Does It Matter?

DTIC Science & Technology

2007-01-01

and/or the general public. Based on this framework, our analysis then compares the char- acteristics of military and civilian respondents using a...armed forces, three major force structure reviews (1990 Base Force, 1993 Bottom-Up Review, 1997 Quadrennial Defense Review) took place in the space...Defense Planning in a Decade of Change: Lessons from the Base Force, Bottom-Up Review, and Quadrennial Defense Review, Santa Monica, CA: RAND
Evaluation of force-torque displays for use with space station telerobotic activities

NASA Technical Reports Server (NTRS)

Hendrich, Robert C.; Bierschwale, John M.; Manahan, Meera K.; Stuart, Mark A.; Legendre, A. Jay

1992-01-01

Recent experiments which addressed Space Station remote manipulation tasks found that tactile force feedback (reflecting forces and torques encountered at the end-effector through the manipulator hand controller) does not improve performance significantly. Subjective response from astronaut and non-astronaut test subjects indicated that force information, provided visually, could be useful. No research exists which specifically investigates methods of presenting force-torque information visually. This experiment was designed to evaluate seven different visual force-torque displays which were found in an informal telephone survey. The displays were prototyped in the HyperCard programming environment. In a within-subjects experiment, 14 subjects nullified forces and torques presented statically, using response buttons located at the bottom of the screen. Dependent measures included questionnaire data, errors, and response time. Subjective data generally demonstrate that subjects rated variations of pseudo-perspective displays consistently better than bar graph and digital displays. Subjects commented that the bar graph and digital displays could be used, but were not compatible with using hand controllers. Quantitative data show similar trends to the subjective data, except that the bar graph and digital displays both provided good performance, perhaps do to the mapping of response buttons to display elements. Results indicate that for this set of displays, the pseudo-perspective displays generally represent a more intuitive format for presenting force-torque information.
General Vo Nguyen Giap: Operational Genius or Lucky Amateur

DTIC Science & Technology

1993-05-17

responsibl , rather than superior soldiering and generaisbip by General Giap. The facts do not bear this out. A carefl study of the First Indochina War...rac exhibited toward him personally and Vietnam, as a nation. Hh resolution to remove the French by force and his suspicions of America may have been...anxious to remove the embarassment of World War H boasted they would defeat the Vietminh within a matter of weeks. Shortly thereafter, French forces engaged
Communicating Why: Aligning the Air Force Message

DTIC Science & Technology

2015-02-17

innovation as the Air Force’s HOW, after all the service could not have demonstrated its WHY without it. For example, Lt Col Jimmy Doolittle ...the Doolittle Raid.54 Later in the war, General Doolittle’s first order as the newly appointed commander of the 8th Air Force was to free the...fighters from their strict bomber tether so they could go on the offensive against the German fighters.55 As Doolittle later noted, the German General of
Preparing General Purpose Forces in the United States and British Armies for Counterinsurgent Operations

DTIC Science & Technology

2010-12-10

Operations In Iraq: Planning, Combat, And Occupation,” Thomas Ricks’ Fiasco, and reports by Army historian Major Isaiah Wilson, and former CENCTOM J-4...established Multi-National Forces-Iraq, and Lieutenant General Thomas Metz, commander of the Army’s III Corps, assumed the mantle of Multi-National Corps...Donald P. Wright and Colonel Timothy R. Reese or Thomas Ricks’ Fiasco among other books. 18Dr. Carter Malkasian, “Counterinsurgency in Iraq: May 2003
DOE Office of Scientific and Technical Information (OSTI.GOV)

Unseren, M.A.

A general framework for solving the dynamic load distribution when two manipulators hold a rigid object is proposed. The underspecified problem of solving for the contact forces and torques based on the object`s equations of motion is transformed into a well specified problem. This is accomplished by augmenting the object`s equations of motion with additional equations which relate a new vector variable quantifying the internal contact force and torque degrees of freedom (DOF) as a linear function of the contact forces and torques. The resulting augmented system yields a well specified solution for the contact forces and torques in whichmore » they are separated into their motion inducing and internal components. A particular solution is suggested which enables the designer to conveniently specify what portion of the payload`s mass each manipulator is to bear. It is also shown that the results of the previous work are just a special case of the general load distribution framework described here.« less
Flow and Force Equations for a Body Revolving in a Fluid

NASA Technical Reports Server (NTRS)

Zahm, A. F.

1979-01-01

A general method for finding the steady flow velocity relative to a body in plane curvilinear motion, whence the pressure is found by Bernoulli's energy principle is described. Integration of the pressure supplies basic formulas for the zonal forces and moments on the revolving body. The application of the steady flow method for calculating the velocity and pressure at all points of the flow inside and outside an ellipsoid and some of its limiting forms is presented and graphs those quantities for the latter forms. In some useful cases experimental pressures are plotted for comparison with theoretical. The pressure, and thence the zonal force and moment, on hulls in plane curvilinear flight are calculated. General equations for the resultant fluid forces and moments on trisymmetrical bodies moving through a perfect fluid are derived. Formulas for potential coefficients and inertia coefficients for an ellipsoid and its limiting forms are presented.
Closed loop problems in biomechanics. Part II--an optimization approach.

PubMed

Vaughan, C L; Hay, J G; Andrews, J G

1982-01-01

A closed loop problem in biomechanics may be defined as a problem in which there are one or more closed loops formed by the human body in contact with itself or with an external system. Under certain conditions the problem is indeterminate--the unknown forces and torques outnumber the equations. Force transducing devices, which would help solve this problem, have serious drawbacks, and existing methods are inaccurate and non-general. The purposes of the present paper are (1) to develop a general procedure for solving closed loop problems; (2) to illustrate the application of the procedure; and (3) to examine the validity of the procedure. A mathematical optimization approach is applied to the solution of three different closed loop problems--walking up stairs, vertical jumping and cartwheeling. The following conclusions are drawn: (1) the method described is reasonably successful for predicting horizontal and vertical reaction forces at the distal segments although problems exist for predicting the points of application of these forces; (2) the results provide some support for the notion that the human neuromuscular mechanism attempts to minimize the joint torques and thus, to a certain degree, the amount of muscular effort; (3) in the validation procedure it is desirable to have a force device for each of the distal segments in contact with a fixed external system; and (4) the method is sufficiently general to be applied to all classes of closed loop problems.
Microscopic derivation of particle-based coarse-grained dynamics: Exact expression for memory function

NASA Astrophysics Data System (ADS)

Izvekov, Sergei

2017-03-01

We consider the generalized Langevin equations of motion describing exactly the particle-based coarse-grained dynamics in the classical microscopic ensemble that were derived recently within the Mori-Zwanzig formalism based on new projection operators [S. Izvekov, J. Chem. Phys. 138(13), 134106 (2013)]. The fundamental difference between the new family of projection operators and the standard Zwanzig projection operator used in the past to derive the coarse-grained equations of motion is that the new operators average out the explicit irrelevant trajectories leading to the possibility of solving the projected dynamics exactly. We clarify the definition of the projection operators and revisit the formalism to compute the projected dynamics exactly for the microscopic system in equilibrium. The resulting expression for the projected force is in the form of a "generalized additive fluctuating force" describing the departure of the generalized microscopic force associated with the coarse-grained coordinate from its projection. Starting with this key expression, we formulate a new exact formula for the memory function in terms of microscopic and coarse-grained conservative forces. We conclude by studying two independent limiting cases of practical importance: the Markov limit (vanishing correlations of projected force) and the limit of weak dependence of the memory function on the particle momenta. We present computationally affordable expressions which can be efficiently evaluated from standard molecular dynamics simulations.

Phantom energy mediates a long-range repulsive force.

PubMed

Amendola, Luca

2004-10-29

Scalar field models with nonstandard kinetic terms have been proposed in the context of k inflation, of Born-Infeld Lagrangians, of phantom energy and, more in general, of low-energy string theory. In general, scalar fields are expected to couple to matter inducing a new interaction. In this Letter I derive the cosmological perturbation equations and the Yukawa correction to gravity for such general models. I find three interesting results: first, when the field behaves as phantom energy (equation of state less than -1), then the coupling strength is negative, inducing a long-range repulsive force; second, the dark-energy field might cluster on astrophysical scales; third, applying the formalism to a Brans-Dicke theory with a general kinetic term it is shown that its Newtonian effects depend on a single parameter that generalizes the Brans-Dicke constant.
Saving Coalition Lives and Limbs: Disrupting the Improvised Explosive Device Network in Iraq with Center of Gravity Analysis and Social Network Viral Targeting

DTIC Science & Technology

2008-12-21

63, 73. 64. Evelin Gerda Lindner, ―In Times of In Times of Globalization and Human Rights: Does Humiliation Become the Most Disruptive Force...Force-Protection Issue, General Says.‖ American Forces Press Service, 14 February 2007. Lindner, Evelin Gerda . ―In Times of In Times of
Status of Storm Water Pollution in the United States

DTIC Science & Technology

1994-09-01

71 Appendix C: Air Force Bases That Applied for the Group Permit ......................... 72 Appendix D: E-Mail Message...34......................................... 25 8. Pollutant Bench Mark Values ....................... 26 9. Air Force Bases Impacted by the Proposed "NPDES General Permit For Storm Water...Metals, Cyanide, Phenols .......................... 70 24. Toxic Pollutants and Hazardous Substances ......... 71 25. Air Force Bases That Applied For
Moka with Ristretto

DTIC Science & Technology

2017-11-01

MOKA WITH RISTRETTO ASSURED INFORMATION SECURITY, INC. NOVEMBER 2017 FINAL TECHNICAL REPORT APPROVED FOR PUBLIC RELEASE; DISTRIBUTION UNLIMITED...STINFO COPY AIR FORCE RESEARCH LABORATORY INFORMATION DIRECTORATE AFRL-RI-RS-TR-2017-223  UNITED STATES AIR FORCE  ROME, NY 13441 AIR FORCE...report is available to the general public, including foreign nations. Copies may be obtained from the Defense Technical Information Center (DTIC
NEON VISUALIZATION ENVIRONMENT

DTIC Science & Technology

2017-07-28

STINFO COPY AIR FORCE RESEARCH LABORATORY INFORMATION DIRECTORATE AFRL-RI-RS-TR-2017-143  UNITED STATES AIR FORCE  ROME, NY 13441 AIR FORCE...report is available to the general public, including foreign nationals. Copies may be obtained from the Defense Technical Information Center (DTIC) (http...FOR THE CHIEF ENGINEER: / S / / S / PETER A. JEDRYSIK JULIE BRICHACEK Work Unit Manager Chief, Information Systems Division Information
Mechanics as the Logical Point of Entry for the Enculturation into Scientific Thinking

ERIC Educational Resources Information Center

Carson, Robert; Rowlands, Stuart

2005-01-01

Force in modern classical mechanics is unique, both in terms of its logical character and the conceptual difficulties it causes. Force is well defined by a set of axioms that not only structures mechanics but science in general. Force is also the dominant theme in the "misconceptions" literature and many philosophers and physicists alike have…
Real-time cartesian force feedback control of a teleoperated robot

NASA Technical Reports Server (NTRS)

Campbell, Perry

1989-01-01

Active cartesian force control of a teleoperated robot is investigated. An economical microcomputer based control method was tested. Limitations are discussed and methods of performance improvement suggested. To demonstrate the performance of this technique, a preliminary test was performed with success. A general purpose bilateral force reflecting hand controller is currently being constructed based on this control method.
2005 TACOM APBI - Partnering to Reset, Recapitalize and Restructure the Force

DTIC Science & Technology

2005-10-28

training. 28 Oct 05~APBI ~9~ Force Projection ~ Technology Challenges (cont.) Force Sustainment Systems Develop smart airdrop systems using Global... UART ). General Purpose Electronic Test Equipment (GPETE) Transform multiple conventional GPETE instruments into a single Virtual Instrument with a...Consists of tools and equipment to refill and repair carbon dioxide fire extinguishers. Rapid Runway Repair - Components include sand grid sections
The Toda lattice as a forced integrable system

NASA Technical Reports Server (NTRS)

Hansen, P. J.; Kaup, D. J.

1985-01-01

The analytic properties of the Jost functions for the inverse scattering transform associated with the forced Toda lattice are shown to determine the time evolution of this particular boundary value problem. It is suggested that inverse scattering methods may be used generally to analyze forced integrable systems. Thus an extension of the applicability of the inverse scattering transform is indicated.
Repulsive Casimir effect from extra dimensions and Robin boundary conditions: From branes to pistons

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

Elizalde, E.; Odintsov, S. D.; Institucio Catalana de Recerca i Estudis Avanccats

2009-03-15

We evaluate the Casimir energy and force for a massive scalar field with general curvature coupling parameter, subject to Robin boundary conditions on two codimension-one parallel plates, located on a (D+1)-dimensional background spacetime with an arbitrary internal space. The most general case of different Robin coefficients on the two separate plates is considered. With independence of the geometry of the internal space, the Casimir forces are seen to be attractive for special cases of Dirichlet or Neumann boundary conditions on both plates and repulsive for Dirichlet boundary conditions on one plate and Neumann boundary conditions on the other. For Robinmore » boundary conditions, the Casimir forces can be either attractive or repulsive, depending on the Robin coefficients and the separation between the plates, what is actually remarkable and useful. Indeed, we demonstrate the existence of an equilibrium point for the interplate distance, which is stabilized due to the Casimir force, and show that stability is enhanced by the presence of the extra dimensions. Applications of these properties in braneworld models are discussed. Finally, the corresponding results are generalized to the geometry of a piston of arbitrary cross section.« less
Unaccompanied Asylum-Seeking Refugee Children's Forced Repatriation: Social Workers' and Police Officers' Health and Job Characteristics.

PubMed

Sundqvist, Johanna; Hansson, Jonas; Ghazinour, Mehdi; Ögren, Kenneth; Padyab, Mojgan

2015-04-19

During the past ten years the number of unaccompanied asylum-seeking refugee children has dramatically increased in Sweden. Some of them are permitted to stay in the receiving country, but some are forced back to their country of origin. Social workers and police officers are involved in these forced repatriations, and such complex situations may cause stressful working conditions. This study aimed to bridge the gap in knowledge of the relationship between general mental health and working with unaccompanied asylum-seeking refugee children who are due for forced repatriation. In addition, the role of psychosocial job characteristics in such relationships was investigated. A questionnaire including sociodemographic characteristics, the Swedish Demand-Control-Support Questionnaire, and the 12-item General Mental Health Questionnaire were distributed nationally. Univariate and multivariable regression models were used. Poorer mental health was associated with working with unaccompanied asylum-seeking refugee children among social workers but not among police officers. Psychological job demand was a significant predictor for general mental health among social workers, while psychological job demand, decision latitude, and marital status were predictors among police officers. Findings are discussed with special regard to the context of social work and police professions in Sweden.
Generalized derivation of the added-mass and circulatory forces for viscous flows

NASA Astrophysics Data System (ADS)

Limacher, Eric; Morton, Chris; Wood, David

2018-01-01

The concept of added mass arises from potential flow analysis and is associated with the acceleration of a body in an inviscid irrotational fluid. When shed vorticity is modeled as vortex singularities embedded in this irrotational flow, the associated force can be superimposed onto the added-mass force due to the linearity of the governing Laplace equation. This decomposition of force into added-mass and circulatory components remains common in modern aerodynamic models, but its applicability to viscous separated flows remains unclear. The present work addresses this knowledge gap by presenting a generalized derivation of the added-mass and circulatory force decomposition which is valid for a body of arbitrary shape in an unbounded, incompressible fluid domain, in both two and three dimensions, undergoing arbitrary motions amid continuous distributions of vorticity. From the general expression, the classical added-mass force is rederived for well-known canonical cases and is seen to be additive to the circulatory force for any flow. The formulation is shown to be equivalent to existing theoretical work under the specific conditions and assumptions of previous studies. It is also validated using a numerical simulation of a pitching plate in a steady freestream flow, conducted by Wang and Eldredge [Theor. Comput. Fluid Dyn. 27, 577 (2013), 10.1007/s00162-012-0279-5]. In response to persistent confusion in the literature, a discussion of the most appropriate physical interpretation of added mass is included, informed by inspection of the derived equations. The added-mass force is seen to account for the dynamic effect of near-body vorticity and is not (as is commonly claimed) associated with the acceleration of near-body fluid which "must" somehow move with the body. Various other consequences of the derivation are discussed, including a concept which has been labeled the conservation of image-vorticity impulse.
Black Holes and the Information Paradox

NASA Astrophysics Data System (ADS)

't Hooft, Gerard

In electromagnetism, like charges repel, opposite charges attract. A remarkable feature of the gravitational force is that like masses attract. This gives rise to an instability: the more mass you have, the stronger the attractive force, until an inevitable implosion follows, leading to a "black hole". It is in the black hole where an apparent conflict between Einstein's General Relativity and the laws of Quantum Mechanics becomes manifest. Most physicists now agree that a black hole should be described by a Schrödinger equation, with a Hermitean Hamiltonian, but this requires a modification of general relativity. Both General Relativity and Quantum mechanics are shaking on their foundations.
Diffusion in the special theory of relativity.

PubMed

Herrmann, Joachim

2009-11-01

The Markovian diffusion theory is generalized within the framework of the special theory of relativity. Since the velocity space in relativity is a hyperboloid, the mathematical stochastic calculus on Riemanian manifolds can be applied but adopted here to the velocity space. A generalized Langevin equation in the fiber space of position, velocity, and orthonormal velocity frames is defined from which the generalized relativistic Kramers equation in the phase space in external force fields is derived. The obtained diffusion equation is invariant under Lorentz transformations and its stationary solution is given by the Jüttner distribution. Besides, a nonstationary analytical solution is derived for the example of force-free relativistic diffusion.
[Impact and forecasting of hepatitis A immunization in French armed forces, 1990-2004].

PubMed

Richard, V; Haus, R; Verret, C; Molinier, S; Hugard, L; Nicand, E; Spiegel, A; Buisson, Y

2006-10-01

Hepatitis A is a public health problem specially for migrants or travellers from industrialized countries with a low hepatitis A endemic level. French armed forces adopted an immunization strategy which first targeted overseas forces and subsequently was extended to all armed forces. In this work we studied the impact of this policy. Epidemiological surveillance data from 1990 to 2004 was analyzed by Poisson regression and exponential models of decrease used to forecast future rates. From the 826 cases of hepatitis A reported during the study period, 266 (32.2%) occurred in overseas forces and 560 (67.8%) in forces stationed in France. Three periods could be identified in the decline of annual incidence: before 1994, with an average rate of 23.2 per 100,000; from 1994 to 1998: 10.2; and after 1998: 1.2 for all French armed forces. For overseas armed forces, the average rate was 117 per 100,000 before 1994 and 17.1 from 1994 to 1998 (p<0.001). For armed forces stationed in France, the average rate was 12.2 per 100,000 before 1998 and 0.9 after (p<0.001). For overseas armed forces, models clearly described the declining incidence subsequent to targeted immunization in 1995 and for armed forces stationed in France, the decline with generalized immunization starting in 1998. The impact of immunization against hepatitis A virus was significant both in an overseas population and in a population staying in France where the risk level can be considered low due to the low endemic rate in France. These results suggest that immunization should be proposed not only for travellers but also for the general population based on real knowledge of the situation and cost-effectiveness analyses.
mm_par2.0: An object-oriented molecular dynamics simulation program parallelized using a hierarchical scheme with MPI and OPENMP

NASA Astrophysics Data System (ADS)

Oh, Kwang Jin; Kang, Ji Hoon; Myung, Hun Joo

2012-02-01

We have revised a general purpose parallel molecular dynamics simulation program mm_par using the object-oriented programming. We parallelized the revised version using a hierarchical scheme in order to utilize more processors for a given system size. The benchmark result will be presented here. New version program summaryProgram title: mm_par2.0 Catalogue identifier: ADXP_v2_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADXP_v2_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: Standard CPC license, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 2 390 858 No. of bytes in distributed program, including test data, etc.: 25 068 310 Distribution format: tar.gz Programming language: C++ Computer: Any system operated by Linux or Unix Operating system: Linux Classification: 7.7 External routines: We provide wrappers for FFTW [1], Intel MKL library [2] FFT routine, and Numerical recipes [3] FFT, random number generator, and eigenvalue solver routines, SPRNG [4] random number generator, Mersenne Twister [5] random number generator, space filling curve routine. Catalogue identifier of previous version: ADXP_v1_0 Journal reference of previous version: Comput. Phys. Comm. 174 (2006) 560 Does the new version supersede the previous version?: Yes Nature of problem: Structural, thermodynamic, and dynamical properties of fluids and solids from microscopic scales to mesoscopic scales. Solution method: Molecular dynamics simulation in NVE, NVT, and NPT ensemble, Langevin dynamics simulation, dissipative particle dynamics simulation. Reasons for new version: First, object-oriented programming has been used, which is known to be open for extension and closed for modification. It is also known to be better for maintenance. Second, version 1.0 was based on atom decomposition and domain decomposition scheme [6] for parallelization. However, atom decomposition is not popular due to its poor scalability. On the other hand, domain decomposition scheme is better for scalability. It still has a limitation in utilizing a large number of cores on recent petascale computers due to the requirement that the domain size is larger than the potential cutoff distance. To go beyond such a limitation, a hierarchical parallelization scheme has been adopted in this new version and implemented using MPI [7] and OPENMP [8]. Summary of revisions: (1) Object-oriented programming has been used. (2) A hierarchical parallelization scheme has been adopted. (3) SPME routine has been fully parallelized with parallel 3D FFT using volumetric decomposition scheme [9]. K.J.O. thanks Mr. Seung Min Lee for useful discussion on programming and debugging. Running time: Running time depends on system size and methods used. For test system containing a protein (PDB id: 5DHFR) with CHARMM22 force field [10] and 7023 TIP3P [11] waters in simulation box having dimension 62.23 Å×62.23 Å×62.23 Å, the benchmark results are given in Fig. 1. Here the potential cutoff distance was set to 12 Å and the switching function was applied from 10 Å for the force calculation in real space. For the SPME [12] calculation, K, K, and K were set to 64 and the interpolation order was set to 4. To do the fast Fourier transform, we used Intel MKL library. All bonds including hydrogen atoms were constrained using SHAKE/RATTLE algorithms [13,14]. The code was compiled using Intel compiler version 11.1 and mvapich2 version 1.5. Fig. 2 shows performance gains from using CUDA-enabled version [15] of mm_par for 5DHFR simulation in water on Intel Core2Quad 2.83 GHz and GeForce GTX 580. Even though mm_par2.0 is not ported yet for GPU, its performance data would be useful to expect mm_par2.0 performance on GPU. Timing results for 1000 MD steps. 1, 2, 4, and 8 in the figure mean the number of OPENMP threads. Timing results for 1000 MD steps from double precision simulation on CPU, single precision simulation on GPU, and double precision simulation on GPU.
Factors Influencing Interdisciplinary Team Member Agreement With Social Worker Assessments of Domestic Violence Incidents in the United States Air Force

DTIC Science & Technology

2002-08-01

General Accounting Office (GAO) noted, "the programs were little more than administrative mechanisms to formalize the existing structure" (Daley, 1999...p. 57). The USAF formalized the DoD Directive by establishing the Air Force Family Advocacy Program (FAP) later that year through Air Force...highly formalized authority structure has served the military well and allows for consistency despite frequent turnover of a mobile personnel force. The
Toward Development of an Integrated Aerospace Power Doctrine.

DTIC Science & Technology

1999-03-01

W. Ashy, Howell M. Estes III, and Richard B. Myers. 33 Air Force in 2025," Grant Hammond claims, "Space Command is to the US Air Force today as the...special program, like special operations"(1 32). General Richard Myers (USAF), current USCINCSPACE, thinks the questioning of the Air Force’s leadership of...be unavailable"(33:42-3). Air Force Historian Richard Hallion has implied functions by describing doctrine as being "the binder, the adhesive
Annual Report of the Secretary of Defense on Reserve Forces for Fiscal Year 1975

DTIC Science & Technology

1976-06-08

acquisition and distribution of equipment continued to be achieved. Progress was made in both filling uxisting shortfalls and in modernization and... progress of the KOTC flight instruction programs. vArmy Air Force Units Participating 200 56 161 Students Enrolled 412 436 2,036 Students Completed 321 361...Resurve Forces IV Current Status and Progress Made in 4 Strengthening the Reserve Components * A. General 4 1. 24 Division rorce 4 4ii 2. Total Force
Maximizing the Potential of the Special Operations Forces and General Purpose Forces

DTIC Science & Technology

2014-05-22

States (Washington, DC: Government Printing Office, 2013), I-15). 8David Tucker and Christopher J. Lamb , United States Special Operations Forces...functionally it was a messy misapplication of forces, that got the job done in a highly inefficient manner. 59Mets, 114. 60Chris Lamb , “Belief Systems and...Taking out the planes was a standoff operation, a job for a three-man team equipped with AT-4s ( shoulder -fired rockets) and machine guns,’ he

Satisfaction with civilian family medicine residency training: Perspectives from serving general duty medical officers in the Canadian Armed Forces.

PubMed

Wolfrom, Brent; Hodgetts, Geoff; Kotecha, Jyoti; Pollock, Emily; Martin, Mary; Han, Han; Morissette, Pierre

2016-09-01

To evaluate satisfaction with civilian residency training programs among serving general duty medical officers within the Canadian Armed Forces. A 23-item, cross-sectional survey face-validated by the office of the Surgeon General of the Canadian Armed Forces. Canada. General duty medical officers serving in the Canadian Armed Forces as of February 2014 identified through the Directorate of Health Services Personnel of the Canadian Forces Health Services Group Headquarters. Satisfaction with and time spent in 7 domains of training: trauma, critical care, emergency medicine, psychiatry, occupational health, sports medicine, and base clinic training. Overall preparedness for leading a health care team, caring for a military population, working in isolated and challenging environments, and being deployed were evaluated on a 5-point Likert scale. Among the survey respondents (n = 135, response rate 54%), 77% agreed or strongly agreed that their family medicine residency training was relevant to their role as a general duty medical officer. Most respondents were either satisfied or very satisfied with their emergency medicine training (77%) and psychiatry training (63%), while fewer were satisfied or very satisfied with their sports medicine (47%), base clinic (41%), and critical care (43%) training. Even fewer respondents were satisfied or very satisfied with their trauma (26%) and occupational health (12%) training. Regarding overall preparedness, 57% believed that they were adequately prepared to care for a military patient population, and 52% of respondents believed they were prepared for their first posting. Fewer respondents (38%) believed they were prepared to work in isolated, austere, or challenging environments, and even fewer (32%) believed that residency training prepared them to lead a health care team. General duty medical officers were satisfied with many aspects of their family medicine residency training; however, military-specific areas for improvement were identified. Many of these areas might be addressed within the context of a 2-year residency program without risking the generalist nature of family medicine training. These findings provide valuable data for residency programs that accept military trainees across the country. Copyright© the College of Family Physicians of Canada.
An Assessment of the Methods Used to Determine Resource Requirements for Enlisted Initial Entry Training.

DTIC Science & Technology

1980-05-01

policy and force structure to insure currency with changes which occur too late to be considered in the PIA process. The Active Army requirements plus...Army Trainees) Outputs Inputs General Skill Training 60,632 70,220 General Intelligence Skill Training 1,406 1,496 Crypto /SIGNINT Related Skill...Skill Training: Manpower = 352 + .234 W - CRYPTO /SIGINT Skill Training: Manpower = 486 + .237 W o Air Force (HQ USAF and ATC formula): A Instructors A
Fickle Allies: Regular and Irregular Confederate Forces in Missouri during the American Civil War

DTIC Science & Technology

2014-05-22

238-239, 242. 58Kel N. Pickens, “The Battle of Wilson’s Creek, Missouri, August 10, 1861,” in Civil War Battles in the West, ed. LeRoy H. Fischer ...force with nearby Confederate Army Brigadier General William Hardee and MSG Brigadier General M. Jeff . Thompson, and open a new front to ultimately...West, ed. LeRoy H. Fischer (Manhattan, KS: Sunflower University Press, 1981), 40. 101Shea, War in the West, 18-19, 26, 34-35. 30
The Impact of US Forces in Korea

DTIC Science & Technology

1987-01-01

190-193. 13. Kim Chum, The Korean War, pp. 187-188. 14. Chu Yong -bok, "How Longing," Dong-A Ilbo, July 10, 1952. p. 2. Chu was a former People’s Army...those who provided comments and suggestions were Brigadier General Kim Jung Whan, formerly colonel, Combined Forces Com- mand, ROK/US; Brigadier General...Korean Defense College faculty; and two class- mates at the Korean Military Academy (class of 1965), Colonel Park Yong Ok, of the Korean Defense
Air Power Versus a Fielded Force: The Misty Facs Of Vietnam and the A-10 Facs of Kosovo a Comparative Analysis

DTIC Science & Technology

2002-06-01

gravity identified by General Norman Schwarzkopf, the U.S. Joint Forces Commander, were the seven elite Republican Guard divisions held in reserve along...Gulf War Air Power Survey Summary Report, (Washington, D.C.: Government Printing Office [GPO], 1993), 12. 6General Norman Schwarzkopf and Peter Petre...author, 28 November 2000. 20William L. Smallwood , Warthog: Flying the A-10 in the Gulf War, (Washington, D.C.: Brassey’s, 1993), 123-24. 66 the
A Man for All Reason: General Larry D. Welch, 12th Chief of Staff, US Air Force

DTIC Science & Technology

2012-06-01

Winton for his countless hours improving my writing. I especially want to thank Generals Larry D. Welch, Charles G. Boyd, John A. Shaud, and...the armed services, limiting both resources and options. Walter Boyne characterized the climate as requiring “some of the most farsighted - and in...many ways difficult - planning in Air Force history.”6 Boyne credited Welch as being just the man capable of performing this task. Welch and his
A Review of the Army’s Modular Force Structure

DTIC Science & Technology

2011-01-01

was a subsequent desire by then–U.S. Army Chief of Staff (CSA, 1999–2003) Gen- eral Eric K. Shinseki for a responsive, mobile, midweight (that is...validation. The objective stage, during which implementation of the force would occur, was set to begin in 2005.15 When General Eric K. Shinseki became...Force—A Relevant Concept? Ft. Leavenworth, Kan.: School of Advanced Military Studies, April 1999, pp. 12–13. 16 General Eric K. Shinseki, U.S. Army
[Towards an unified theory of the universe basic forces ("the everything theory")].

PubMed

Aguilar Peris, José

2004-01-01

Numerous efforts have been made in order to unify all the basic forces in nature. In 1967 the fusion of electromagnetic and weak forces was obtained and in 1973 a theoretical bridge between the electroweak and the strong forces have been constructed. This theory is waiting for experimental proofs in the CERN large hadron collider. The last stage would be "the everything theory", which includes the gravitational force. Only the so called superstring theory is a good candidate to overcome the incompatibility of the quantum mechanics and the general relativity, but this theory is not already achieved.
Compilation of FY 1997 Air Force General Funds Consolidated Financial Statements at the Defense Finance and Accounting Service Denver Center.

DTIC Science & Technology

1998-10-05

Consolidated Financial Statements to the Air Force Audit Agency. The Defense Finance and Accounting Service Denver Center maintained accounting records and prepared the FY 1997 financial statements for the Air Force. More than $343 billion in total assets was reported at year’s end in these statements, and total revenues for the year exceeded $64 billion. The Air Force Audit Agency disclaimed an opinion on these statements. Additionally, although the Office of Management and Budget does not require budgetary resource reporting until FY 1998, the Air Force
van der Waals torque and force between anisotropic topological insulator slabs

NASA Astrophysics Data System (ADS)

Lu, Bing-Sui

2018-01-01

We investigate the character of the van der Waals (vdW) torque and force between two coplanar and dielectrically anisotropic topological insulator (TI) slabs separated by a vacuum gap in the nonretardation regime, where the optic axes of the slabs are each perpendicular to the normal direction to the slab-gap interface and also generally differently oriented from each other. We find that in addition to the magnetoelectric coupling strength, the anisotropy can also influence the sign of the vdW force, viz., a repulsive vdW force can become attractive if the anisotropy is increased sufficiently. In addition, the vdW force oscillates as a function of the angular difference between the optic axes of the TI slabs, being most repulsive/least attractive (least repulsive/most attractive) for angular differences that are integer (half-integer) multiples of π . Our third finding is that the vdW torque for TI slabs is generally weaker than that for ordinary dielectric slabs. Our work provides an instance in which the vector potential appears in a calculation of the vdW interaction for which the limit is nonretarded or static.
Report of the Special Task Force to Study Not-for-Profit Hospitals and Unsponsored Charity Care.

PubMed

Anderson, R J; Milburn, L T

1990-04-01

Texas not-for-profit hospitals recently received intense scrutiny regarding their involvement in charity-related contributions when Texas Attorney General Jim Mattox formed the Task Force to Study Not-for-Profit Hospitals and Unsponsored Charity Care. This article details the task force's recommendations concerning charity care obligations of Texas not-for-profit hospitals. Setting the stage for these recommendations was a broad definition of charitable services that included costs for delivering services to indigents and for providing community services to fulfill the hospital's charitable, religious, educational, research, or eleemosynary purposes. The task force unanimously agreed that a mandated level of charity care was incongruent with the hospitals' individual missions and specific community needs, but they supported the formation of standard accounting procedures for charitable services and the voluntary submission of their mission statements to the attorney general of Texas. While the hospitals' role in providing charitable services is very important, the task force emphasized that the overall need for adequate financing and reimbursement of health care is a societal problem that needs specific state and federal actions.
Einstein's 1919 View

NASA Astrophysics Data System (ADS)

Goradia, Shantilal

2012-10-01

When Rutherford discovered the nuclear force in 1919, he felt the force he discovered reflected some deviation of Newtonian gravity. Einstein too in his 1919 paper published the failure of the general relativity and Newtonian gravity to explain nuclear force and, in his concluding remarks, he retracted his earlier introduction of the cosmological constant. Consistent with his genius, we modify Newtonian gravity as probabilistic gravity using natural Planck units for a realistic study of nature. The result is capable of expressing both (1) nuclear force [strong coupling], and (2) Newtonian gravity in one equation, implying in general, in layman's words, that gravity is the cumulative effect of all quantum mechanical forces which are impossible to measure at long distances. Non discovery of graviton and quantum gravity silently support our findings. Continuing to climb on the shoulders of the giants enables us to see horizons otherwise unseen, as reflected in our book: ``Quantum Consciousness - The Road to Reality,'' and physics/0210040, where we derive the fine structure constant as a function of the age of the universe in Planck times consistent with Gamow's hint, using natural logarithm consistent with Feynman's hint.
A generalized modal shock spectra method for spacecraft loads analysis. [internal loads in a spacecraft structure subjected to a dynamic launch environment

NASA Technical Reports Server (NTRS)

Trubert, M.; Salama, M.

1979-01-01

Unlike an earlier shock spectra approach, generalization permits an accurate elastic interaction between the spacecraft and launch vehicle to obtain accurate bounds on the spacecraft response and structural loads. In addition, the modal response from a previous launch vehicle transient analysis with or without a dummy spacecraft - is exploited to define a modal impulse as a simple idealization of the actual forcing function. The idealized modal forcing function is then used to derive explicit expressions for an estimate of the bound on the spacecraft structural response and forces. Greater accuracy is achieved with the present method over the earlier shock spectra, while saving much computational effort over the transient analysis.
Implementation of the force decomposition machine for molecular dynamics simulations.

PubMed

Borštnik, Urban; Miller, Benjamin T; Brooks, Bernard R; Janežič, Dušanka

2012-09-01

We present the design and implementation of the force decomposition machine (FDM), a cluster of personal computers (PCs) that is tailored to running molecular dynamics (MD) simulations using the distributed diagonal force decomposition (DDFD) parallelization method. The cluster interconnect architecture is optimized for the communication pattern of the DDFD method. Our implementation of the FDM relies on standard commodity components even for networking. Although the cluster is meant for DDFD MD simulations, it remains general enough for other parallel computations. An analysis of several MD simulation runs on both the FDM and a standard PC cluster demonstrates that the FDM's interconnect architecture provides a greater performance compared to a more general cluster interconnect. Copyright © 2012 Elsevier Inc. All rights reserved.
Deficiencies in Journal Vouchers that Affected the FY 2009 Air Force General Fund Statement of Budgetary Resources

DTIC Science & Technology

2011-12-01

internal control over financial reporting to: • properly support reconciliations with specific accounting transactions and discontinue forcing...agreement of amounts to meet budgetary financial reporting requirements; • include adequate detailed evidence with journal vouchers so that audit trails...Finding A. Forced Journal Voucher Adjustments Weaken the Reliability of Financial Reporting 5 Reimbursable Activity Adjustments Need Detailed
The Dynamics of Finite-Dimensional Systems Under Nonconservative Position Forces

NASA Astrophysics Data System (ADS)

Lobas, L. G.

2001-01-01

General theorems on the stability of stationary states of mechanical systems subjected to nonconservative position forces are presented. Specific mechanical problems on gyroscopic systems, a double-link pendulum with a follower force and elastically fixed upper tip, multilink pneumowheel vehicles, a monorail car, and rail-guided vehicles are analyzed. Methods for investigation of divergent bifurcations and catastrophes of stationary states are described
Relative motion of orbiting particles under the influence of perturbing forces. Volume 1: Summary

NASA Technical Reports Server (NTRS)

Eades, J. B., Jr.

1974-01-01

The relative motion for orbiting vehicles, under the influence of various perturbing forces, has been studied to determine what influence these inputs, and others, can have. The analytical tasks are discribed in general terms; the force types considered, are outlined modelled and simulated, and the capabilities of the computer programs which have evolved in support of this work are denoted.
Coast Guard SOF

DTIC Science & Technology

2006-02-01

Forces units into known Viet Cong (VC) strongholds, participating in direct action raids on VC junk bases, conducting psychological operations, and...and General McClure established the Army’s Psychological Warfare Cen- ter and 10th Special Forces Group in 1952.62 President Kennedy’s interest in...counterinsurgency warfare paved the way for the “Green Beret,” for which Army Special Forces renamed the Psychological Warfare Center the JFK Special
General Chemistry for Engineers.

ERIC Educational Resources Information Center

Kybett, B. D.

1982-01-01

Discusses the relationship between molecular structure, intermolecular forces, and tensile strengths of a polymer and suggests that this is a logical way to introduce polymers into a general chemistry course. (Author/JN)
14 CFR 23.321 - General.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false General. 23.321 Section 23.321 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... General. (a) Flight load factors represent the ratio of the aerodynamic force component (acting normal to...

14 CFR 23.321 - General.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 1 2012-01-01 2012-01-01 false General. 23.321 Section 23.321 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... General. (a) Flight load factors represent the ratio of the aerodynamic force component (acting normal to...
14 CFR 23.321 - General.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false General. 23.321 Section 23.321 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS... General. (a) Flight load factors represent the ratio of the aerodynamic force component (acting normal to...
A general contact mechanical formulation of multilayered structures and its application to deconvolute thickness/mechanical properties of glue used in surface force apparatus.

PubMed

Math, Souvik; Horn, Roger; Jayaram, Vikram; Biswas, Sanjay Kumar

2007-04-15

Currently data obtained from surface force apparatus experiments are convoluted with the mechanical response of glue of unknown thickness, used to bond mica sheets to the substrates. This paper describes a formulation to precisely deconvolute out the forces between the mica sheets by determining the thickness of glue, knowing the mechanical properties of the glue. The formulation consists of a general solution based on the noniterative Hankel transform of the Laplace equation. The generality is achieved by treating all the layers except the one in contact as an effective lumped system consisting of a set of springs in series, where each spring represents a layer. The solution is validated by nanoindentation of trilayer systems consisting of layers with widely diverse mechanical properties, some differing from each other by three orders of magnitude. SFA experiments are done with carefully metered slabs of glue. The proposed method is validated by comparing the actual glue thicknesses with those determined using the present analysis.
On the Dynamical Behavior of the Cysteine Dioxygenase-l-Cysteine Complex in the Presence of Free Dioxygen and l-Cysteine.

PubMed

Pietra, Francesco

2017-11-01

In this work, viable models of cysteine dioxygenase (CDO) and its complex with l-cysteine dianion were built for the first time, under strict adherence to the crystal structure from X-ray diffraction studies, for all atom molecular dynamics (MD). Based on the CHARMM36 FF, the active site, featuring an octahedral dummy Fe(II) model, allowed us observing water exchange, which would have escaped attention with the more popular bonded models. Free dioxygen (O 2 ) and l-cysteine, added at the active site, could be observed being expelled toward the solvating medium under Random Accelerated Molecular Dynamics (RAMD) along major and minor pathways. Correspondingly, free dioxygen (O 2 ), added to the solvating medium, could be observed to follow the same above pathways in getting to the active site under unbiased MD. For the bulky l-cysteine, 600 ns of trajectory were insufficient for protein penetration, and the molecule was stuck at the protein borders. These models pave the way to free energy studies of ligand associations, devised to better clarify how this cardinal enzyme behaves in human metabolism. © 2017 Wiley-VHCA AG, Zurich, Switzerland.
ACPYPE - AnteChamber PYthon Parser interfacE.

PubMed

Sousa da Silva, Alan W; Vranken, Wim F

2012-07-23

ACPYPE (or AnteChamber PYthon Parser interfacE) is a wrapper script around the ANTECHAMBER software that simplifies the generation of small molecule topologies and parameters for a variety of molecular dynamics programmes like GROMACS, CHARMM and CNS. It is written in the Python programming language and was developed as a tool for interfacing with other Python based applications such as the CCPN software suite (for NMR data analysis) and ARIA (for structure calculations from NMR data). ACPYPE is open source code, under GNU GPL v3, and is available as a stand-alone application at http://www.ccpn.ac.uk/acpype and as a web portal application at http://webapps.ccpn.ac.uk/acpype. We verified the topologies generated by ACPYPE in three ways: by comparing with default AMBER topologies for standard amino acids; by generating and verifying topologies for a large set of ligands from the PDB; and by recalculating the structures for 5 protein-ligand complexes from the PDB. ACPYPE is a tool that simplifies the automatic generation of topology and parameters in different formats for different molecular mechanics programmes, including calculation of partial charges, while being object oriented for integration with other applications.
Time-resolved fluorescence of thioredoxin single-tryptophan mutants: modeling experimental results with minimum perturbation mapping

NASA Astrophysics Data System (ADS)

Silva, Norberto D., Jr.; Haydock, Christopher; Prendergast, Franklyn G.

1994-08-01

The time-resolved fluorescence decay of single tryptophan (Trp) proteins is typically described using either a distribution of lifetimes or a sum of two or more exponential terms. A possible interpretation for this fluorescence decay heterogeneity is the existence of different isomeric conformations of Trp about its (chi) +1) and (chi) +2) dihedral angles. Are multiple Trp conformations compatible with the remainder of the protein in its crystallographic configuration or do they require repacking of neighbor side chains? It is conceivable that isomers of the neighbor side chains interconvert slowly on the fluorescence timescale and contribute additional lifetime components to the fluorescence intensity. We have explored this possibility by performing minimum perturbation mapping simulations of Trp 28 and Trp 31 in thioredoxin (TRX) using CHARMm 22. Mappings of Trp 29 and Trp 31 give the TRX Trp residue energy landscape as a function of (chi) +1) and (chi) +2) dihedral angles. Time-resolved fluorescence intensity and anisotropy decay of mutant TRX (W28F and W31F) are measured and interpreted in light of the above simulations. Relevant observables, like order parameters and isomerization rates, can be derived from the minimum perturbation maps and compared with experiment.
Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.

PubMed

Sakkal, Leon A; Rajkowski, Kyle Z; Armen, Roger S

2017-06-05

Following insights from recent crystal structures of the muscarinic acetylcholine receptor, binding modes of Positive Allosteric Modulators (PAMs) were predicted under the assumption that PAMs should bind to the extracellular surface of the active state. A series of well-characterized PAMs for adenosine (A 1 R, A 2A R, A 3 R) and muscarinic acetylcholine (M 1 R, M 5 R) receptors were modeled using both rigid and flexible receptor CHARMM-based molecular docking. Studies of adenosine receptors investigated the molecular basis of the probe-dependence of PAM activity by modeling in complex with specific agonist radioligands. Consensus binding modes map common pharmacophore features of several chemical series to specific binding interactions. These models provide a rationalization of how PAM binding slows agonist radioligand dissociation kinetics. M 1 R PAMs were predicted to bind in the analogous M 2 R PAM LY2119620 binding site. The M 5 R NAM (ML-375) was predicted to bind in the PAM (ML-380) binding site with a unique induced-fit receptor conformation. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
Lessons learned from comparing molecular dynamics engines on the SAMPL5 dataset.

PubMed

Shirts, Michael R; Klein, Christoph; Swails, Jason M; Yin, Jian; Gilson, Michael K; Mobley, David L; Case, David A; Zhong, Ellen D

2017-01-01

We describe our efforts to prepare common starting structures and models for the SAMPL5 blind prediction challenge. We generated the starting input files and single configuration potential energies for the host-guest in the SAMPL5 blind prediction challenge for the GROMACS, AMBER, LAMMPS, DESMOND and CHARMM molecular simulation programs. All conversions were fully automated from the originally prepared AMBER input files using a combination of the ParmEd and InterMol conversion programs. We find that the energy calculations for all molecular dynamics engines for this molecular set agree to better than 0.1 % relative absolute energy for all energy components, and in most cases an order of magnitude better, when reasonable choices are made for different cutoff parameters. However, there are some surprising sources of statistically significant differences. Most importantly, different choices of Coulomb's constant between programs are one of the largest sources of discrepancies in energies. We discuss the measures required to get good agreement in the energies for equivalent starting configurations between the simulation programs, and the energy differences that occur when simulations are run with program-specific default simulation parameter values. Finally, we discuss what was required to automate this conversion and comparison.
Lessons learned from comparing molecular dynamics engines on the SAMPL5 dataset

PubMed Central

Shirts, Michael R.; Klein, Christoph; Swails, Jason M.; Yin, Jian; Gilson, Michael K.; Mobley, David L.; Case, David A.; Zhong, Ellen D.

2017-01-01

We describe our efforts to prepare common starting structures and models for the SAMPL5 blind prediction challenge. We generated the starting input files and single configuration potential energies for the host-guest in the SAMPL5 blind prediction challenge for the GROMACS, AMBER, LAMMPS, DESMOND and CHARMM molecular simulation programs. All conversions were fully automated from the originally prepared AMBER input files using a combination of the ParmEd and InterMol conversion programs. We find that the energy calculations for all molecular dynamics engines for this molecular set agree to a better than 0.1% relative absolute energy for all energy components, and in most cases an order of magnitude better, when reasonable choices are made for different cutoff parameters. However, there are some surprising sources of statistically significant differences. Most importantly, different choices of Coulomb’s constant between programs are one of the largest sources of discrepancies in energies. We discuss the measures required to get good agreement in the energies for equivalent starting configurations between the simulation programs, and the energy differences that occur when simulations are run with program-specific default simulation parameter values. Finally, we discuss what was required to automate this conversion and comparison. PMID:27787702
Lessons learned from comparing molecular dynamics engines on the SAMPL5 dataset

NASA Astrophysics Data System (ADS)

Shirts, Michael R.; Klein, Christoph; Swails, Jason M.; Yin, Jian; Gilson, Michael K.; Mobley, David L.; Case, David A.; Zhong, Ellen D.

2017-01-01

We describe our efforts to prepare common starting structures and models for the SAMPL5 blind prediction challenge. We generated the starting input files and single configuration potential energies for the host-guest in the SAMPL5 blind prediction challenge for the GROMACS, AMBER, LAMMPS, DESMOND and CHARMM molecular simulation programs. All conversions were fully automated from the originally prepared AMBER input files using a combination of the ParmEd and InterMol conversion programs. We find that the energy calculations for all molecular dynamics engines for this molecular set agree to better than 0.1 % relative absolute energy for all energy components, and in most cases an order of magnitude better, when reasonable choices are made for different cutoff parameters. However, there are some surprising sources of statistically significant differences. Most importantly, different choices of Coulomb's constant between programs are one of the largest sources of discrepancies in energies. We discuss the measures required to get good agreement in the energies for equivalent starting configurations between the simulation programs, and the energy differences that occur when simulations are run with program-specific default simulation parameter values. Finally, we discuss what was required to automate this conversion and comparison.
Is extreme bite performance associated with extreme morphologies in sharks?

PubMed

Huber, Daniel R; Claes, Julien M; Mallefet, Jérôme; Herrel, Anthony

2009-01-01

As top predators in many oceanic communities, sharks are known to eat large prey and are supposedly able to generate high bite forces. This notion has, however, largely gone untested due to the experimental intractability of these animals. For those species that have been investigated, it remains unclear whether their high bite forces are simply a consequence of their large body size or the result of diet-related adaptation. As aquatic poikilotherms, sharks can grow very large, making them ideal subjects with which to investigate the effects of body size on bite force. Relative bite-force capacity is often associated with changes in head shape because taller or wider heads can, for example, accommodate larger jaw muscles. Constraints on bite force in general may also be released by changes in tooth shape. For example, more pointed teeth may allow a predator to penetrate prey more effectively than blunt, pavementlike teeth. Our analyses show that large sharks do not bite hard for their body size, but they generally have larger heads. Head width is the best predictor of bite force across the species included in our study as indicated by a multiple regression model. Contrary to our predictions, sharks with relatively high bite forces for their body size also have relatively more pointed teeth at the front of the tooth row. Moreover, species including hard prey in their diet are characterized by high bite forces and narrow and pointed teeth at the jaw symphysis.
Verified solutions for the gravitational attraction to an oblate spheroid: Implications for planet mass and satellite orbits

NASA Astrophysics Data System (ADS)

Hofmeister, Anne M.; Criss, Robert E.; Criss, Everett M.

2018-03-01

Forces external to the oblate spheroid shape, observed from planetary to galactic scales, are demonstrably non-central, which has important ramifications for planetary science. We simplify historic formulae and derive new analytical solutions for the gravitational potential and force outside a constant density oblate. Numerical calculations that sum point mass contributions in a >109 element mesh confirm our equations. We show that contours of constant force and potential about oblate bodies are closely approximated by two confocal families whose foci (f) respectively are (9/10)½ae and (3/5)½ae for a body with f = ae. This leads to useful approximations that address internal density variations. We demonstrate that the force on a general point is not directed towards the oblate's center, nor are forces simply proportional to the inverse square of that distance, despite forces in the equatorial and axial directions pointing towards the center. Our results explain complex dynamics of galactic systems. Because most planets and stars have an aspect ratio >0.9, the spherical approximation is reasonable except for orbits within ∼2 body radii. We show that applying the "generalized" potential, which assumes central forces, yields J2 values half those expected for oblate bodies, and probably underestimates masses of Uranus and Neptune by ∼0.2%. We show that the inner Saturnian moons are subject to non-central forces, which may affect calculations of their orbital precession. Our new series should improve interpretation of flyby data.
Forces involved in bacterial adhesion to hydrophilic and hydrophobic surfaces.

PubMed

Boks, Niels P; Norde, Willem; van der Mei, Henny C; Busscher, Henk J

2008-10-01

Using a parallel-plate flow chamber, the hydrodynamic shear forces to prevent bacterial adhesion (F(prev)) and to detach adhering bacteria (F(det)) were evaluated for hydrophilic glass, hydrophobic, dimethyldichlorosilane (DDS)-coated glass and six different bacterial strains, in order to test the following three hypotheses. 1. A strong hydrodynamic shear force to prevent adhesion relates to a strong hydrodynamic shear force to detach an adhering organism. 2. A weak hydrodynamic shear force to detach adhering bacteria implies that more bacteria will be stimulated to detach by passing an air-liquid interface (an air bubble) through the flow chamber. 3. DLVO (Derjaguin, Landau, Verwey, Overbeek) interactions determine the characteristic hydrodynamic shear forces to prevent adhesion and to detach adhering micro-organisms as well as the detachment induced by a passing air-liquid interface. F(prev) varied from 0.03 to 0.70 pN, while F(det) varied from 0.31 to over 19.64 pN, suggesting that after initial contact, strengthening of the bond occurs. Generally, it was more difficult to detach bacteria from DDS-coated glass than from hydrophilic glass, which was confirmed by air bubble detachment studies. Calculated attractive forces based on the DLVO theory (F(DLVO)) towards the secondary interaction minimum were higher on glass than on DDS-coated glass. In general, all three hypotheses had to be rejected, showing that it is important to distinguish between forces acting parallel (hydrodynamic shear) and perpendicular (DLVO, air-liquid interface passages) to the substratum surface.
Generalized Faxén's theorem: Evaluating first-order (hydrodynamic drag) and second-order (acoustic radiation) forces on finite-sized rigid particles, bubbles and droplets in arbitrary complex flows

NASA Astrophysics Data System (ADS)

Annamalai, Subramanian; Balachandar, S.

2016-11-01

In recent times, study of complex disperse multiphase problems involving several million particles (e.g. volcanic eruptions, spray control etc.) is garnering momentum. The objective of this work is to present an accurate model (termed generalized Faxén's theorem) to predict the hydrodynamic forces on such inclusions (particles/bubbles/droplets) without having to solve for the details of flow around them. The model is developed using acoustic theory and the force obtained as a summation of infinite series (monopole, dipole and higher sources). The first-order force is the time-dependent hydrodynamic drag force arising from the dipole component due to interaction between the gas and the inclusion at the microscale level. The second-order force however is a time-averaged differential force (contributions arise both from monopole and dipole), also known as the acoustic radiation force primarily used to levitate particles. In this work, the monopole and dipole strengths are represented in terms of particle surface and volume averages of the incoming flow properties and therefore applicable to particle sizes of the order of fluid length scale and subjected to any arbitrary flow. Moreover, this model can also be used to account for inter-particle coupling due to neighboring particles. U.S. DoE, NNSA, Advanced Simulation and Computing Program, Cooperative Agreement under PSAAP-II, Contract No. DE-NA0002378.
FAST TRACK COMMUNICATION: Criticality-induced universality in ratchets

NASA Astrophysics Data System (ADS)

Chacón, Ricardo

2010-08-01

Conclusive mathematical arguments are presented supporting the ratchet conjecture (Chacón 2007 J. Phys. A: Math. Theor. 40 F413), i.e. the existence of a universal force waveform which optimally enhances directed transport by symmetry breaking. Specifically, such a particular waveform is shown to be unique for both temporal and spatial biharmonic forces, and general (non-perturbative) laws providing the dependence of the strength of directed transport on the force parameters are deduced for these forces. The theory explains previous results for a great diversity of systems subjected to such biharmonic forces and provides a universal quantitative criterion to optimize any application of the ratchet effect induced by symmetry breaking of temporal and spatial biharmonic forces.
Reducing uncertainties in energy dissipation measurements in atomic force spectroscopy of molecular networks and cell-adhesion studies.

PubMed

Biswas, Soma; Leitao, Samuel; Theillaud, Quentin; Erickson, Blake W; Fantner, Georg E

2018-06-20

Atomic force microscope (AFM) based single molecule force spectroscopy (SMFS) is a valuable tool in biophysics to investigate the ligand-receptor interactions, cell adhesion and cell mechanics. However, the force spectroscopy data analysis needs to be done carefully to extract the required quantitative parameters correctly. Especially the large number of molecules, commonly involved in complex networks formation; leads to very complicated force spectroscopy curves. One therefore, generally characterizes the total dissipated energy over a whole pulling cycle, as it is difficult to decompose the complex force curves into individual single molecule events. However, calculating the energy dissipation directly from the transformed force spectroscopy curves can lead to a significant over-estimation of the dissipated energy during a pulling experiment. The over-estimation of dissipated energy arises from the finite stiffness of the cantilever used for AFM based SMFS. Although this error can be significant, it is generally not compensated for. This can lead to significant misinterpretation of the energy dissipation (up to the order of 30%). In this paper, we show how in complex SMFS the excess dissipated energy caused by the stiffness of the cantilever can be identified and corrected using a high throughput algorithm. This algorithm is then applied to experimental results from molecular networks and cell-adhesion measurements to quantify the improvement in the estimation of the total energy dissipation.
Toward Automated Benchmarking of Atomistic Force Fields: Neat Liquid Densities and Static Dielectric Constants from the ThermoML Data Archive.

PubMed

Beauchamp, Kyle A; Behr, Julie M; Rustenburg, Ariën S; Bayly, Christopher I; Kroenlein, Kenneth; Chodera, John D

2015-10-08

Atomistic molecular simulations are a powerful way to make quantitative predictions, but the accuracy of these predictions depends entirely on the quality of the force field employed. Although experimental measurements of fundamental physical properties offer a straightforward approach for evaluating force field quality, the bulk of this information has been tied up in formats that are not machine-readable. Compiling benchmark data sets of physical properties from non-machine-readable sources requires substantial human effort and is prone to the accumulation of human errors, hindering the development of reproducible benchmarks of force-field accuracy. Here, we examine the feasibility of benchmarking atomistic force fields against the NIST ThermoML data archive of physicochemical measurements, which aggregates thousands of experimental measurements in a portable, machine-readable, self-annotating IUPAC-standard format. As a proof of concept, we present a detailed benchmark of the generalized Amber small-molecule force field (GAFF) using the AM1-BCC charge model against experimental measurements (specifically, bulk liquid densities and static dielectric constants at ambient pressure) automatically extracted from the archive and discuss the extent of data available for use in larger scale (or continuously performed) benchmarks. The results of even this limited initial benchmark highlight a general problem with fixed-charge force fields in the representation low-dielectric environments, such as those seen in binding cavities or biological membranes.
Are inertial forces ever of significance in cricket, golf and other sports?

NASA Astrophysics Data System (ADS)

Robinson, Garry; Robinson, Ian

2017-04-01

In previous papers we investigated the motion of a spherical projectile rotating about an arbitrary axis, subject to a drag force, a lift or Magnus force, and in the presence of a wind. The aim was to determine the motion of balls used in sporting games, primarily cricket. Newton’s laws of motion apply in an inertial (unaccelerated) coordinate system, but the rotating Earth is not an inertial system. In such a non-inertial system two additional forces are present, the Coriolis force which produces a side-ways movement, and the centrifugal force. Generally these two inertial forces produce noticeable effects only on the large scale, when either the time of travel and/or the path length is large. In this paper we have added both of these forces to the equations of motion. In addition, we have also included a ground friction force in order to simulate a ball rolling over a surface or, more generally, a body moving through a resistive medium such as water. Here we quantitatively investigate the magnitude and direction of the effect of the inertial forces in a number of cases. It is found that, as expected, the effects of the inertial forces are generally small for ball games. In cricket the side-ways movement is ≲1 cm for a throw from the boundary and ≲1 mm for a slow bowler’s delivery, and for a long drive in golf it is ≲10 cm. In lawn bowls the side-ways movement can be ∼2.8 cm, which may be significant, given the nature of this sport. The inertial forces are also potentially of relevance in sporting events not employing spherical projectiles. For example, in Olympic rowing we find that the side-ways movement can be more than 40 m for a 2 km race if it is not compensated for, and nearly 20 m for a 4 min mile event in athletics. The effect is also of significance in events such as swimming and horse racing. The importance of this is that athletes may not be aware of the effect and, in the case of rowing for example, may attribute it to side-ways currents, winds, or a deficiency in their rowing style. As a further complication, the magnitude of the side-ways movement is latitude dependent and its direction is hemisphere dependent, being to the right in the northern hemisphere and to the left in the southern hemisphere.
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