scholarly journals Force-Field Benchmarking by Alternatives: A Systematic Study of Ten Small α- and β-Proteins

2020 ◽  
Author(s):  
Kalyanashis Jana ◽  
Kasper P. Kepp
Keyword(s):  
Phase Space ◽  
Force Field ◽  
Tertiary Structure ◽  
Force Fields ◽  
Local Structures ◽  
Full Phase Space ◽  
Structure Relationship ◽  
Sampling Problem ◽  
Dynamics Simulations ◽  
Almost All

AbstractPredicting protein structure from sequence is a central challenge of biochemistry, yet different force fields feature distinct structural biases that are hard to quantify, preventing clear assessment of results. Since structural transitions occur on milliseconds to seconds, sampling is out of reach in almost all routine studies, we inherently rely on local sampled structures, and benchmarks have emphasized the ability to reproduce these local structures. Here we approach the force field bias problem in a different way, via alternatives, by revisiting the old question: How unique is the sequence-structure relationship when studied computationally? To circumvent the sampling problem, the system-bias (specific structure choices affect apparent force field structural preference) and the complexity of tertiary structure, we studied ten small α- and β-proteins (20-35 amino acids) with one helix or sheet. For each of the ten sequences, we then designed alternative β- or α-structures and subjected all 20 proteins to molecular dynamics simulations. We apply this “alternative structure” benchmark to five of the best modern force fields: Amber ff99SB-ILDN, Amber ff99SB*-ILDN, CHARMM22*, CHARMM36, and GROMOS54A8. Surprisingly, we find that all sequences with reported β-structures also feature stable native-like α-structures with all five force fields. In contrast, only the alternative β-1T5Q and to some extent β-1CQ0 and β-1V1D resembled native β-proteins. With full phase space sampling being impossible in almost all cases, our benchmark by alternatives, which samples another local part of phase space in direct comparison, is a useful complement to millisecond benchmarks when these become more common.

scholarly journals W-RESP: Well-Restrained Electrostatic Potential Derived Charges. Revisiting the Charge Derivation Model

2020 ◽  
Author(s):  
Michal Janeček ◽  
Petra Kührová ◽  
Vojtěch Mlýnský ◽  
Michal Otyepka ◽  
Jiří Šponer ◽  
...  
Keyword(s):  
Force Field ◽  
Electrostatic Potential ◽  
Electrostatic Interactions ◽  
Force Fields ◽  
Amber Force Field ◽  
Heterocyclic Molecules ◽  
Partial Charges ◽  
Grid Points ◽  
Dynamics Simulations ◽  
Extra Point

ABSTRACTRepresentation of electrostatic interactions by a Coulombic pair-wise potential between atom-centered partial charges is a fundamental and crucial part of empirical force fields used in classical molecular dynamics simulations. The broad success of the AMBER force field family originates mainly from the restrained electrostatic potential (RESP) charge model, which derives partial charges to reproduce the electrostatic field around the molecules. However, description of the electrostatic potential around molecules by standard RESP may be biased for some types of molecules. In this study, we modified the RESP charge derivation model to improve its description of the electrostatic potential around molecules, and thus electrostatic interactions in the force field. In particular, we re-optimized the atomic radii for definition of the grid points around the molecule, redesigned the restraining scheme and included extra point charges. The RESP fitting was significantly improved for aromatic heterocyclic molecules. Thus, the suggested W-RESP(-EP) charge derivation model showed clear potential for improving the performance of the nucleic acid force fields, for which poor description of nonbonded interactions, such as underestimated base pairing, makes it difficult to describe the folding free energy landscape of small oligonucleotides.

scholarly journals Kinetic pathways of water exchange in the first hydration shell of magnesium: Influence of water model and ionic force field

2021 ◽  
Author(s):  
Sebastian Falkner ◽  
Nadine Schwierz
Keyword(s):  
Force Field ◽  
Water Exchange ◽  
Force Fields ◽  
Hydration Shell ◽  
Water Model ◽  
Polarizable Force Fields ◽  
Ionic Force ◽  
Influence Of Water ◽  
Biomolecular Simulations ◽  
Dynamics Simulations

Water exchange between the first and second hydration shell is essential for the role of Mg2+ in biochemical processes. In order to provide microscopic insights into the exchange mechanism, we resolve the exchange pathways by all-atom molecular dynamics simulations and transition path sampling. Since the exchange kinetics relies on the choice of the water model and the ionic force field, we systematically investigate the influence of seven different polarizable and non-polarizable water and three different Mg2+ models. In all cases, water exchange can occur either via an indirect or direct mechanism (exchanging molecules occupy different/same position on water octahedron). In addition, the results reveal a crossover from an interchange dissociative (Id) to an associative (Ia) reaction mechanism dependent on the range of the Mg2+-water interaction potential of the respective force field. Standard non-polarizable force fields follow the Id mechanism in agreement with experimental results. By contrast, polarizable and long-ranged non-polarizable force fields follow the Ia mechanism. Our results provide a comprehensive view on the influence of the water model and ionic force field on the exchange dynamics and the foundation to assess the choice of the force field in biomolecular simulations.

scholarly journals Predicting NMR Relaxation of Proteins from Molecular Dynamics Simulations with Accurate Methyl Rotation Barriers

2020 ◽  
Author(s):  
Falk Hoffmann ◽  
Frans Mulder ◽  
Lars V. Schäfer
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Force Fields ◽  
Nmr Relaxation ◽  
Md Simulations ◽  
Quantitative Agreement ◽  
Relaxation Rates ◽  
Protein Force Fields ◽  
Dynamics Simulations ◽  
Methyl Rotation

The internal dynamics of proteins occurring on time scales from picoseconds to nanoseconds can be sensitively probed by nuclear magnetic resonance (NMR) spin relaxation experiments, as well as by molecular dynamics (MD) simulations. This complementarity offers unique opportunities, provided that the two methods are compared at a suitable level. Recently, several groups have used MD simulations to compute the spectral density of backbone and side-chain molecular motions, and to predict NMR relaxation rates from these. Unfortunately, in the case of methyl groups in protein side-chains, inaccurate energy barriers to methyl rotation were responsible for a systematic discrepancy in the computed relaxation rates, as demonstrated for the AMBER ff99SB*-ILDN force field (and related parameter sets), impairing quantitative agreement between simulations and experiments. However, correspondence could be regained by emending the MD force field with accurate coupled cluster quantum chemical calculations. Spurred by this positive result, we tested whether this approach could be generally applicable, in spite of the fact that different MD force fields employ different water models. Improved methyl group rotation barriers for the CHARMM36 and AMBER ff15ipq protein force fields were derived, such that the NMR relaxation data obtained from the MD simulations now also display very good agreement with experiment. Results herein showcase the performance of present-day MD force fields, and manifest their refined ability to accurately describe internal protein dynamics.

scholarly journals How well do force fields capture the strength of salt bridges in proteins?

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4967 ◽  
Author(s):  
Mustapha Carab Ahmed ◽  
Elena Papaleo ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Force Fields ◽  
Salt Bridge ◽  
Dynamics Simulation ◽  
Ionic Interactions ◽  
Salt Bridges ◽  
Important Interaction ◽  
The Stability ◽  
Dynamics Simulations

Salt bridges form between pairs of ionisable residues in close proximity and are important interactions in proteins. While salt bridges are known to be important both for protein stability, recognition and regulation, we still do not have fully accurate predictive models to assess the energetic contributions of salt bridges. Molecular dynamics simulation is one technique that may be used study the complex relationship between structure, solvation and energetics of salt bridges, but the accuracy of such simulations depends on the force field used. We have used NMR data on the B1 domain of protein G (GB1) to benchmark molecular dynamics simulations. Using enhanced sampling simulations, we calculated the free energy of forming a salt bridge for three possible lysine-carboxylate ionic interactions in GB1. The NMR experiments showed that these interactions are either not formed, or only very weakly formed, in solution. In contrast, we show that the stability of the salt bridges is overestimated, to different extents, in simulations of GB1 using seven out of eight commonly used combinations of fixed charge force fields and water models. We also find that the Amber ff15ipq force field gives rise to weaker salt bridges in good agreement with the NMR experiments. We conclude that many force fields appear to overstabilize these ionic interactions, and that further work may be needed to refine our ability to model quantitatively the stability of salt bridges through simulations. We also suggest that comparisons between NMR experiments and simulations will play a crucial role in furthering our understanding of this important interaction.

scholarly journals Predicting NMR Relaxation of Proteins from Molecular Dynamics Simulations with Accurate Methyl Rotation Barriers

2019 ◽  
Author(s):  
Falk Hoffmann ◽  
Frans Mulder ◽  
Lars V. Schäfer
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Force Fields ◽  
Nmr Relaxation ◽  
Md Simulations ◽  
Quantitative Agreement ◽  
Relaxation Rates ◽  
Protein Force Fields ◽  
Dynamics Simulations ◽  
Methyl Rotation

The internal dynamics of proteins occurring on time scales from picoseconds to nanoseconds can be sensitively probed by nuclear magnetic resonance (NMR) spin relaxation experiments, as well as by molecular dynamics (MD) simulations. This complementarity offers unique opportunities, provided that the two methods are compared at a suitable level. Recently, several groups have used MD simulations to compute the spectral density of backbone and side-chain molecular motions, and to predict NMR relaxation rates from these. Unfortunately, in the case of methyl groups in protein side-chains, inaccurate energy barriers to methyl rotation were responsible for a systematic discrepancy in the computed relaxation rates, as demonstrated for the AMBER ff99SB*-ILDN force field (and related parameter sets), impairing quantitative agreement between simulations and experiments. However, correspondence could be regained by emending the MD force field with accurate coupled cluster quantum chemical calculations. Spurred by this positive result, we tested whether this approach could be generally applicable, in spite of the fact that different MD force fields employ different water models. Improved methyl group rotation barriers for the CHARMM36 and AMBER ff15ipq protein force fields were derived, such that the NMR relaxation data obtained from the MD simulations now also display very good agreement with experiment. Results herein showcase the performance of present-day MD force fields, and manifest their refined ability to accurately describe internal protein dynamics.

scholarly journals Predicting NMR Relaxation of Proteins from Molecular Dynamics Simulations with Accurate Methyl Rotation Barriers

2019 ◽  
Author(s):  
Falk Hoffmann ◽  
Frans Mulder ◽  
Lars V. Schäfer
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Force Fields ◽  
Nmr Relaxation ◽  
Md Simulations ◽  
Quantitative Agreement ◽  
Relaxation Rates ◽  
Protein Force Fields ◽  
Dynamics Simulations ◽  
Methyl Rotation

The internal dynamics of proteins occurring on time scales from picoseconds to nanoseconds can be sensitively probed by nuclear magnetic resonance (NMR) spin relaxation experiments, as well as by molecular dynamics (MD) simulations. This complementarity offers unique opportunities, provided that the two methods are compared at a suitable level. Recently, several groups have used MD simulations to compute the spectral density of backbone and side-chain molecular motions, and to predict NMR relaxation rates from these. Unfortunately, in the case of methyl groups in protein side-chains, inaccurate energy barriers to methyl rotation were responsible for a systematic discrepancy in the computed relaxation rates, as demonstrated for the AMBER ff99SB*-ILDN force field (and related parameter sets), impairing quantitative agreement between simulations and experiments. However, correspondence could be regained by emending the MD force field with accurate coupled cluster quantum chemical calculations. Spurred by this positive result, we tested whether this approach could be generally applicable, in spite of the fact that different MD force fields employ different water models. Improved methyl group rotation barriers for the CHARMM36 and AMBER ff15ipq protein force fields were derived, such that the NMR relaxation data obtained from the MD simulations now also display very good agreement with experiment. Results herein showcase the performance of present-day MD force fields, and manifest their refined ability to accurately describe internal protein dynamics.

Introducing QUBE: Quantum Mechanical Bespoke Force Fields for Protein Simulations

2019 ◽  
Author(s):  
Alice Allen ◽  
Michael J. Robertson ◽  
Michael C. Payne ◽  
Daniel Cole
Keyword(s):  
Force Field ◽  
Force Fields ◽  
Specific Protein ◽  
Biological Molecules ◽  
Quantum Mechanical ◽  
Conformational Preferences ◽  
J Coupling ◽  
Force Field Parameters ◽  
Folded Proteins ◽  
Dynamics Simulations

<div><div><div><p>Molecular mechanics force field parameters for macromolecules, such as proteins, are traditionally fit to reproduce experimental properties of small molecules, and thus they neglect system-specific polarization. In this paper, we introduce a complete QUantum mechanical BEspoke (QUBE) protein force field, which derives non-bonded parameters directly from the electron density of the specific protein under study. The main backbone and sidechain protein torsional parameters are re-derived in this work by fitting to quantum mechanical dihedral scans for compatibibility with QUBE non-bonded parameters. Software is provided for the preparation of QUBE input files. The accuracy of the new force field, and the derived torsional parameters, are tested by comparing the conformational preferences of a range of peptides and proteins with experimental measurements. Accurate backbone and sidechain conformations are obtained in molecular dynamics simulations of dipeptides, with NMR J coupling errors comparable to the widely-used OPLS force field. In simulations of five folded proteins, the secondary structure is generally retained and the NMR J coupling errors are similar to standard transferable force fields, although some loss of the experimental structure is observed in certain regions of the proteins. Overall, with several avenues for further development, the use of system-specific non-bonded force field parameters is a promising approach for next-generation simulations of biological molecules.</p></div></div></div>

scholarly journals Comparing Dimerization Free Energies and Binding Modes of Small Aromatic Molecules with Different Force Fields

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6069
Author(s):  
Ilias Patmanidis ◽  
Riccardo Alessandri ◽  
Alex H. de de Vries ◽  
Siewert J. Marrink
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Force Fields ◽  
Supramolecular Assembly ◽  
Model Systems ◽  
Binding Modes ◽  
Free Energies ◽  
Care Needs ◽  
Strength Of Interaction ◽  
Dynamics Simulations

Dimerization free energies are fundamental quantities that describe the strength of interaction of different molecules. Obtaining accurate experimental values for small molecules and disentangling the conformations that contribute most to the binding can be extremely difficult, due to the size of the systems and the small energy differences. In many cases, one has to resort to computational methods to calculate such properties. In this work, we used molecular dynamics simulations in conjunction with metadynamics to calculate the free energy of dimerization of small aromatic rings, and compared three models from popular online servers for atomistic force fields, namely G54a7, CHARMM36 and OPLS. We show that, regardless of the force field, the profiles for the dimerization free energy of these compounds are very similar. However, significant care needs to be taken when studying larger molecules, since the deviations from the trends increase with the size of the molecules, resulting in force field dependent preferred stacking modes; for example, in the cases of pyrene and tetracene. Our results provide a useful background study for using topology builders to model systems which rely on stacking of aromatic moieties, and are relevant in areas ranging from drug design to supramolecular assembly.

FOLDING FREE ENERGY LANDSCAPE OF THE DECAPEPTIDE CHIGNOLIN

2008 ◽  
Vol 22 (31) ◽  
pp. 3087-3098 ◽  
Author(s):  
XIANGHUA DOU ◽  
JIHUA WANG
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Force Fields ◽  
Energy Landscapes ◽  
Native Structure ◽  
Good Template ◽  
Free Energy Landscapes ◽  
Folded Structures ◽  
Dynamics Simulations ◽  
Folding Free Energy

Chignolin is an artificially designed ten-residue (GYDPETGTWG) folded peptide, which is the smallest protein and provides a good template for protein folding. In this work, we completed four explicit water molecular dynamics simulations of Chignolin folding using GROMOS and OPLS-AA force fields from extended initial states without any experiment informations. The four-folding free energy landscapes of the peptide has been drawn. The folded state of Chignolin has been successfully predicated based on the free energy landscapes. The four independent simulations gave similar results. (i) The four free energy landscapes have common characters. They are fairly smooth, barrierless, funnel-like and downhill without intermediate state, which consists with the experiment. (ii) The different extended initial structures converge at similar folded structures with the lowest free energy under GROMOS and OPLS-AA force fields. In the GROMOS force field, the backbone RMSD of the folded structures from the NMR native structure of Chignolin is only 0.114 nm, which is a stable structure in this force field. In the OPLS-AA force field, the similar results have been obtained. In addition, the smallest RMSD structure is in better agreement with the NMR native structure but unlikely stable in the force field.

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