Force field influence on the observation of π-helical protein structures in molecular dynamics simulations

In this study, we have investigated the sampling of pi-helical conformations, with i, i + 5 hydrogen bonding, using empirical force fields. From replica exchange molecular dynamics simulations of the helical peptide acetyl-(AAQAA)(3)-amide using the CHARMM22 force field and implicit solvent, we find rapid conversion from an initial alpha-helix to pi-helical conformations. While this confirms similar studies of different peptides in explicit solvent, it does not agree with experimental data where pi-helices are rarely observed. The sampling of pi-helices is significantly diminished in favor of canonical alpha-helices when a newly extended CHARMM22/CMAP force field is used, where the backbone dihedral phi/psi potential map in a vacuum is matched exactly to high-level quantum mechanical data for an alanine dipeptide model system. Energetic analysis shows that the difference between alpha- and pi-helical conformations of the alanine dipeptide in a vacuum is 2.6 kcal/mol according to quantum mechanical calculations while both conformations are energetically equivalent in the unmodified CHARMM22 potential. Similar trends are also found in a number of other empirical force fields, suggesting that the observation of pi-helical conformations in molecular dynamics simulations is mostly a force field artifact.