Residue-specific α-helix propensities from molecular simulation.

Formation of α-helices is a fundamental process in protein folding and assembly. By studying helix formation in molecular simulations of a series of alanine-based peptides, we obtain the temperature-dependent α-helix propensities of all 20 naturally occurring residues with two recent additive force fields, Amber ff03w and Amber ff99SB(∗). Encouragingly, we find that the overall helix propensity of many residues is captured well by both energy functions, with Amber ff99SB(∗) being more accurate. Nonetheless, there are some residues that deviate considerably from experiment, which can be attributed to two aspects of the energy function: i), variations of the charge model used to determine the atomic partial charges, with residues whose backbone charges differ most from alanine tending to have the largest error; ii), side-chain torsion potentials, as illustrated by the effect of modifications to the torsion angles of I, L, D, N. We find that constrained refitting of residue charges for charged residues in Amber ff99SB(∗) significantly improves their helix propensity. The resulting parameters should more faithfully reproduce helix propensities in simulations of protein folding and disordered proteins.