A Test on Peptide Stability of AMBER Force Fields with Implicit Solvation

Abstract

We used replica exchange molecular dynamics (REMD) simulations to evaluate four different AMBER force fields and three different implicit solvent models. Our aim was to determine if these physics-based models captured the correct secondary structures of two α-helical and two β-peptides: the 14-mer EK helix of Baldwin and co-workers, the C-terminal helix of ribonuclease, the 16-mer C-terminal hairpin of protein G, and the trpzip2 miniprotein. The different models gave different results, but generally we found that AMBER ff96 plus the implicit solvent model of Onufriev, Bashford, and Case gave reasonable structures, and is fairly well-balanced between helix and sheet. We also observed differences in the strength of ion pairing in the solvent models, we but found that the native secondary structures were retained even when salt bridges were prevented in the conformational sampling. Overall, this work indicates that some of these all-atom physics-based force fields may be good starting points for protein folding and protein structure prediction. I. Are Physics-Based Force Fields Accurate Enough for Protein Structure Predictions?All-atom force fields, such as CHARMM, 1 AMBER, 2,3 and OPLS, 4 are widely used for computer simulations of the properties of proteins and small peptides. However, such force fields are not yet commonly used to predict native protein structures, in part because of computational limitations in the conformational sampling of systems with many degrees of freedom, as in proteins, but also in part because of concerns that the force fields themselves might not be good enough. It has been difficult to distinguish whether physics-based protein structure prediction has been hindered by insufficient sampling or by limitations in the force fields.However, a few tests on protein structure prediction have been possible so far because of mechanistically focused sampling or large dedicated computer resources. There are some notable successes indicating that modern physics-based force fields might be accurate enough to predict the native structures of proteins. Using supercomputer resources, Duan and Kollman performed a milestone microsecond molecular dynamics simulation of the 36-residue villin *Corresponding author. E-mail: E-mail: shell@engineering.ucsb.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript headpiece in explicit solvent starting from an unfolded conformation. 5 Scheraga's group, starting from a random configuration, folded the 46-residue protein A to within 3.5 Å rootmean-square deviation (rmsd) using Monte Carlo dynamics with an implicit solvation model. 6 Another milestone was the folding of villin by the Pande group on Folding@Home, a distributed grid computing system running on the screen savers of volunteer computers worldwide. 7Recently, higher accuracies have also been achieved. High-resolution structures of villin have recently been reached by Pande et al. 8 and Duan et al. 9,10 In addition, three groups have folded the 20-residue...

Evaluating force field accuracy with long-time simulations of a β-hairpin tryptophan zipper peptide

“…Force fields employing the ff96 dihedral parameters have produced at least qualitatively accurate results for trpzip2, 11,14,15,39 and our results fall into agreement with these. Furthermore, our study of W2W9 provides evidence for the robustness of these parameters in modeling β-hairpin structures.…”

“…In an implicit solvent, and holding other conditions constant, we have observed a substantial sensitivity in folding behavior to variation of the φ and ψ dihedral potential energies, consistent with other studies that have signaled such sensitivity in α-helical and β-sheet peptides in the context of AMBER force fields. [5][6][7]14 In particular, while ff99SB dihedral energies do not support a stable native state for trpzip2 in the given simulation conditions, those derived from ff96 do so quite well, which is also well supported. 11,14,15,39 Through simulations of the W2W9 mutant, we have found that these backbone parameters are not sufficient for a high degree of hairpin stability; electrostatic and van der Waals side chain interactions are also critical.…”

“…[5][6][7]14 In particular, while ff99SB dihedral energies do not support a stable native state for trpzip2 in the given simulation conditions, those derived from ff96 do so quite well, which is also well supported. 11,14,15,39 Through simulations of the W2W9 mutant, we have found that these backbone parameters are not sufficient for a high degree of hairpin stability; electrostatic and van der Waals side chain interactions are also critical. Moreover, our results with W2W9 compare well with experiment, suggesting that W96 is robust in modeling β-hairpin structures.…”

“…Among the latter, several have demonstrated stability and folding of trpzip models using OPLS-AA, 4, 10 AMBER ff96, [11][12][13][14][15] and AMBER ff99SB (Ref. 16) all-atom molecular mechanics force fields.…”

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

“…A distance-dependent dielectric treatment had been used for many years as a convenient approximation. However, it is a crude approximation for the all-atom model of biomolecules as the solvent effect is of critical importance in determining the stability of the peptide conformation and FEL (Mitomo et al 2006;Shell et al 2008;Zhou and Berne 2002). As such implicit solvent models should be employed carefully.…”