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Optimizing Protein−Solvent Force Fields to Reproduce Intrinsic Conformational Preferences of Model Peptides

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While most force field efforts in biomolecular simulation have focused on the parametrization of the protein, relatively little attention has been paid to the quality of the accompanying solvent model. These considerations are especially relevant for simulations of intrinsically disordered peptides and proteins, for which energy differences between conformations are small and interactions with water are enhanced. In this work, we investigate the accuracy of the AMBER ff99SB force field when combined with the standard TIP3P model or the more recent TIP4P-Ew water model, to generate conformational ensembles for disordered trialanine (Ala3), triglycine (Gly3), and trivaline (Val3) peptides. We find that the TIP4P-Ew water model yields significantly better agreement with experimentally measured scalar couplings-and therefore more accurate conformational ensembles-for both Ala3 and Gly3. For Val3, however, we find that the TIP3P and TIP4P-Ew ensembles are equivalent in their performance. To further improve the protein-water force field combination and obtain more accurate intrinsic conformational preferences, we derive a straightforward perturbation to the ϕ' backbone dihedral potential that shifts the β-PPII equilibrium. We find that the revised ϕ' backbone dihedral potential yields improved conformational ensembles for a variety of small peptides and maintains the stability of the globular ubiquitin protein in TIP4P-Ew water.

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