Current Status of Protein Force Fields for Molecular Dynamics Simulations

Lopes, Pedro E. M.; Guvench, Olgun; MacKerell, Alexander D.

doi:10.1007/978-1-4939-1465-4_3

Cited by 168 publications

(142 citation statements)

References 129 publications

(156 reference statements)

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“…56 These models tend to be no greater than an order of magnitude more computationally demanding than all-atom additive force fields, allowing for the possibility of sampling thermodynamic ensembles in order to compute free energies. However, since the development of additive force fields is a decade or more ahead of polarizable models, the strengths of weaknesses of the former are better understood, including difficulties handling ions.…”

Section: Discussionmentioning

confidence: 99%

Sulfation and Cation Effects on the Conformational Properties of the Glycan Backbone of Chondroitin Sulfate Disaccharides

Faller

Guvench

2015

J. Phys. Chem. B

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Chondroitin sulfate (CS) is one of several glycosaminoglycans that are major components of proteoglycans. A linear polymer consisting of repeats of the disaccharide -4GlcAβ1-3GalNAcβ1-, CS undergoes differential sulfation resulting in five unique sulfation patterns. Because of the dimer repeat, the CS glycosidic “backbone” has two distinct sets of conformational degrees of freedom defined by pairs of dihedral angles: (ϕ1, ψ1) about the β1-3 glycosidic linkage and (ϕ2, ψ2) about the β1-4 glycosidic linkage. Differential sulfation and the possibility of cation binding, combined with the conformational flexibility and biological diversity of CS, complicate experimental efforts to understand CS three-dimensional structures at atomic resolution. Therefore, all-atom explicit-solvent molecular dynamics simulations with Adaptive Biasing Force sampling of the CS backbone were applied to obtain high resolution, high precision free energies of CS disaccharides as a function of all possible backbone geometries. All ten disaccharides (β1-3 vs. β1-4 linkage x five different sulfation patterns) were studied; additionally, ion effects were investigated by considering each disaccharide in the presence of either neutralizing sodium or calcium cations. GlcAβ1-3GalNAc disaccharides have a single, broad, thermodynamically important free-energy minimum whereas GalNAcβ1-4GlcA disaccharides have two such minima. Calcium cations but not sodium cations bind to the disaccharides, and binding is primarily to the GlcA –COO− moiety as opposed to sulfate groups. This binding alters the glycan backbone thermodynamics in instances where a calcium cation bound to –COO− can act to bridge and stabilize an interaction with an adjacent sulfate group, whereas, in the absence of this cation, the proximity of a sulfate group to –COO− results in two like charges being both desolvated and placed adjacent to each other and is found to be destabilizing. In addition to providing information on sulfation and cation effects, the present results can be applied to building models of CS polymers and as a point of comparison in studies of CS polymer backbone dynamics and thermodynamics.

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Section: Discussionmentioning

confidence: 99%

Sulfation and Cation Effects on the Conformational Properties of the Glycan Backbone of Chondroitin Sulfate Disaccharides

Faller

Guvench

2015

J. Phys. Chem. B

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“…Aðx i ðtÞÞ1 j=σði;tÞ dt, [7] where 1 j=σðiÞ = 1 if j = σðiÞ and 1 j=σðiÞ = 0 otherwise, and similarly for 1 j=σði, tÞ :…”

Section: Significancementioning

confidence: 99%

“…However, exploiting the full potential of MD simulations remains a major challenge, primarily due to approximations in all-atom force fields and the limitation of accessible timescales available to standard MD. Force fields continue to be improved (4)(5)(6)(7), and hardware developments involving special-purpose high-performance computers (8), high-performance graphics processing units (9), or massively parallel simulations (10) also permit us to enlarge the scope of MD simulations. However, it has been argued (11) that algorithm developments will be the key to access biologically relevant timescales with MD.…”

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confidence: 99%

Multiscale implementation of infinite-swap replica exchange molecular dynamics

Abrams

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Replica exchange molecular dynamics (REMD) is a popular method to accelerate conformational sampling of complex molecular systems. The idea is to run several replicas of the system in parallel at different temperatures that are swapped periodically. These swaps are typically attempted every few MD steps and accepted or rejected according to a Metropolis-Hastings criterion. This guarantees that the joint distribution of the composite system of replicas is the normalized sum of the symmetrized product of the canonical distributions of these replicas at the different temperatures. Here we propose a different implementation of REMD in which (i) the swaps obey a continuous-time Markov jump process implemented via Gillespie's stochastic simulation algorithm (SSA), which also samples exactly the aforementioned joint distribution and has the advantage of being rejection free, and (ii) this REMD-SSA is combined with the heterogeneous multiscale method to accelerate the rate of the swaps and reach the so-called infinite-swap limit that is known to optimize sampling efficiency. The method is easy to implement and can be trivially parallelized. Here we illustrate its accuracy and efficiency on the examples of alanine dipeptide in vacuum and C-terminal β-hairpin of protein G in explicit solvent. In this latter example, our results indicate that the landscape of the protein is a triple funnel with two folded structures and one misfolded structure that are stabilized by H-bonds.importance sampling | REMD | SSA | HMM | protein-folding A ll-atom molecular dynamics (MD) simulations are increasingly used as a tool to study the structure and function of large biomolecules and other complex molecular systems from first principles. By allowing us to scrutinize these systems at spatiotemporal resolutions that are typically beyond experimental reach, MD simulations are changing the way we understand chemical and biological processes, and their impact in areas such as chemical engineering, synthetic biology, drug design, and so on is bound to increase in the coming years (1-3). However, exploiting the full potential of MD simulations remains a major challenge, primarily due to approximations in all-atom force fields and the limitation of accessible timescales available to standard MD. Force fields continue to be improved (4-7), and hardware developments involving special-purpose high-performance computers (8), high-performance graphics processing units (9), or massively parallel simulations (10) also permit us to enlarge the scope of MD simulations. However, it has been argued (11) that algorithm developments will be the key to access biologically relevant timescales with MD. In particular, there is a great need for methods capable of accelerating the exploration and sampling of the conformational space of complex molecular systems.Among the various techniques that have been introduced to this end in recent years, replica exchange MD (REMD) (12) remains one of the most popular. The reasons for this success are simple: REMD does not requ...

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“…The CHARMM Drude-2013 FF is similar to the CHARMM additive FF, with the addition of a charged particle within non-hydrogen atoms that moves in response to the electric field, also known as the charge-on-spring [26]. The use of these FFs in protein simulations has been reviewed recently [92], but current parametrization efforts focus mostly on biomolecules in aqueous environments and there is significant work yet to be done towards simulating an interfacial system.…”

Section: Polarizable Force Fields For Interfacial Systemsmentioning

confidence: 99%

Force fields for simulating the interaction of surfaces with biological molecules

et al. 2016

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The interaction of biomolecules with solid interfaces is of fundamental importance to several emerging biotechnologies such as medical implants, anti-fouling coatings and novel diagnostic devices. Many of these technologies rely on the binding of peptides to a solid surface, but a full understanding of the mechanism of binding, as well as the effect on the conformation of adsorbed peptides, is beyond the resolution of current experimental techniques. Nanoscale simulations using molecular mechanics offer potential insights into these processes. However, most models at this scale have been developed for aqueous peptide and protein simulation, and there are no proven models for describing biointerfaces. In this review, we detail the current research towards developing a non-polarizable molecular model for peptide-surface interactions, with a particular focus on fitting the model parameters as well as validation by choice of appropriate experimental data.

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Current Status of Protein Force Fields for Molecular Dynamics Simulations

Cited by 168 publications

References 129 publications

Sulfation and Cation Effects on the Conformational Properties of the Glycan Backbone of Chondroitin Sulfate Disaccharides

Sulfation and Cation Effects on the Conformational Properties of the Glycan Backbone of Chondroitin Sulfate Disaccharides

Multiscale implementation of infinite-swap replica exchange molecular dynamics

Force fields for simulating the interaction of surfaces with biological molecules

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