An accurate representation of solute-water interactions is necessary for molecular dynamics simulations of biomolecules that reside in aqueous environments. Modern force fields and advanced water models describe solute-solute and water-water interactions reasonably accurately but have known shortcomings in describing solute-water interactions, demonstrated by the large differences between calculated and experimental solvation free energies across a range of peptide and drug chemistries. In this work, we introduce a method for optimizing solute-water van der Waals interactions to reproduce experimental solvation free energy data and apply it to the optimization of a fixed charge force field (AMBER ff99SB/GAFF) and advanced water model (TIP4P-Ew). We show that, with these optimizations, the combination of AMBER ff99SB/GAFF and TIP4P-Ew is able to reproduce the solvation free energies of a variety of biologically relevant small molecules to within 1.0 k(B)T. We further validate these optimizations by examining the aggregation propensities of dipeptide-water solutions, the conformational preferences of short disordered peptides, and the native state stability and dynamics of a folded protein.

The interplay of modern molecular simulation and high-quality nuclear magnetic resonance (NMR) experiments has reached a fruitful stage for quantitative characterization of structural ensembles of disordered peptides. Amyloid-β 1–42 (Aβ42), the primary peptide associated with Alzheimer’s disease, and fragments such as Aβ21–30 are both classified as intrinsically disordered peptides (IDPs). We use a variety of NMR observables to validate de novo molecular dynamics simulations in explicit water to characterize the tertiary structure ensemble of Aβ42 and Aβ21–30 from the perspective of their classification as IDPs. Unlike the Aβ21–30 fragment that conforms to expectations of an IDP that is primarily extended, we find that Aβ42 samples conformations reflecting all possible secondary structure categories and spans the range of IDP classifications from collapsed structured states to highly extended conformations, making it an IDP with a far more heterogeneous tertiary ensemble.

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.