How to strike a conformational balance in protein force fields for molecular dynamics simulations?

Abstract

Molecular dynamics (MD) simulation is a powerful tool for exploring the conformational energy landscape of proteins, and the reliability of MD results is crucially dependent on the underlying force field (FF). An accurate FF capable of producing balanced distributions of diverse conformations at multiple levels has been a long‐sought goal. Towards this, several decades of joint efforts have been made to address FF deficiencies, manifested by conformational biases at different levels (local conformations, secondary structures, and global extendedness of polypeptide chain). We first present the major FF biases, then review the strategies to address them separately. Specifically, both nonresidue‐specific and residue‐specific strategies for torsional parameter optimization have been applied to achieve local conformation and secondary structure balances. Significant improvements can be gained with residue‐specific torsional parameters especially when explicit dihedral couplings are considered. Further, the additional balance between protein–protein and protein–water interactions has been optimized via multiple ways to reproduce the global extendedness of polypeptide chains, especially for unfolded or disordered proteins. This review aims to summarize the most valuable experience and lessons gained from the past, which, we hope, can facilitate further improvements of both classical FFs and more sophisticated models such as polarizable FFs. This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Molecular and Statistical Mechanics > Molecular Mechanics

Quantitative prediction of ensemble dynamics, shapes and contact propensities of intrinsically disordered proteins

“…In a significant development, residue-specific force fields have been introduced. [41] These force fields use in addition coil library information from the Protein Data Bank (PDB) by incorporating the individual backbone φ,ψ propensities of each residue type. [41][42][43][44][45][46][47] Such residuespecific force fields, in combination with suitable water models, can provide an improved representation of disordered states while retaining the properties of ordered proteins.…”

Molecular dynamics simulations of an α-synuclein NAC domain fragment with a ff14IDPSFF IDP-specific force field suggest β-sheet intermediate states of fibrillation

“…ff14IDPSFF does not exhibit any helix formation in their conformations and instead adopts b-strands, even b-hairpins, which are formed within the NAC domain itself or together with the amino acids of the N-terminal domain. The cluster 1 centroid has b-strands (residues 1-4, 14-20, 40-42, and 58-61) formed between the NAC and N-terminal domains, and a short b-hairpin (residues [29][30][31][32][33][34][35] in the NAC domain itself. The centroids of clusters 2 and 3 present larger b-hairpins that involved different amino acids of the NAC domain.…”

“…In fact, previous studies on differences between the standard and modern force fields have demonstrated high sensitivity in obtaining IDP conformational ensembles. 28,29 Approaches to include intrinsic disorder can range from adjusting the dihedral parameters (CHARMM22*, 30 RSFF2 31 and OPLS-AA/M 32 force fields), adding a grid-based energy correction term to the ϕ / ψ dihedral energy surface called the CMAP method (CHARMM36, 33 ff14IDPSFF, 34 and ESFF1 35 ) and refining the protein–water interactions (a99SB-disp, 36 ff03ws, 37 and CHARMM36m 38 ). Among these new force fields, ff14IDPSFF has been developed as a promising force field capable of correcting the dihedral distributions of all 20 amino acids from the popular ff14SB 39 force field but assisted using the CMAP method.…”

Quantitative prediction of ensemble dynamics, shapes and contact propensities of intrinsically disordered proteins

“…(41) These force fields use in addition coil library information from the Protein Data Bank (PDB) by incorporating the individual backbone j,y propensities of each residue type. (41)(42)(43)(44)(45)(46)(47) Such residue-specific force fields, in combination with suitable water models, can provide an improved representation of disordered states while retaining the properties of ordered proteins.…”

“…(41) These force fields use in addition coil library information from the Protein Data Bank (PDB) by incorporating the individual backbone φ,ψ propensities of each residue type. (41–47) Such residue-specific force fields, in combination with suitable water models, can provide an improved representation of disordered states while retaining the properties of ordered proteins. With respect to water models, TIP4P-D and closely related derivatives have been notably successful in preventing overly compact conformations by favoring more extended IDP structures showing improved agreement with experiment.…”