Do Molecular Dynamics Force Fields Capture Conformational Dynamics of Alanine in Water?

We examine the ability of six molecular dynamics (MD) force fields (Amber ff14SB, Amber ff99SBnmr1, Amber ff03ws, OPLS-AA/L, OPLS-AA/M, and CHARMM36) to reproduce conformational ensembles of the central alanine in GAG and AAA in a way that is consistent with five (GAG) or six (AAA) J coupling constants and amide I′ profiles. MD-derived Ramachandran plots for all six force fields under study differ from those obtained by the Gaussian fit to experimental data in three major ways: (i) the polyproline II (pPII) basin in the Ramachandran plot is too concentrated, (ii) the antiparallel β (aβ) basin is overpopulated, and (iii) the transitional β (βt) basin is underpopulated. Amber ff14SB outperforms the other five MD force fields and yields the highest pPII populations of the central alanine residue in GAG (55%) and AAA (63%), in good agreement with the predictions of the Gaussian model (59 and 76%). The analysis of the hydration layer around the central alanine residue reveals considerable reorientation of water molecules and reduction in both the average number of water molecules and the average number of water–water hydrogen bonds when glycines (in GAG) are replaced by alanines (in AAA), elucidating water-mediated nearest neighbor effects on alanine’s conformational dynamics.