Evaluating Molecular Mechanical Potentials for Helical Peptides and Proteins.

EJ Thompson, AJ DePaul, SS Patel & EJ Sorin.
PLoS ONE (2010) 5, e10056

Our assessment of biophysical force fields as applied to helical peptides and proteins continues with the comparison of “next generation” AMBER-03 and AMBER-99SB to our previous results, particularly with respect to our AMBER variant, AMBER-99phi. Here we also incorporate simulations of a flexible and largely helical protein in order to assess the ability of these molecular models to adequately stabilize such structures.

Multiple variants of the AMBER all-atom force field were quantitatively evaluated with respect to their ability to accurately characterize helix-coil equilibria in explicit solvent simulations. Using a global distributed computing network, absolute conformational convergence was achieved for large ensembles of the capped A21 and Fs helical peptides. Further assessment of these AMBER variants was conducted via simulations of a flexible 164-residue five-helix-bundle protein, apolipophorin-III, on the 100 ns timescale. Of the contemporary potentials that had not been assessed previously, the AMBER-99SB force field showed significant helix-destabilizing tendencies, with beta bridge formation occurring in helical peptides, and unfolding of apolipophorin-III occurring on the tens of nanoseconds timescale. The AMBER-03 force field, while showing adequate helical propensities for both peptides and stabilizing apolipophorin-III, (i) predicts an unexpected decrease in helicity with ALA to ARG+ substitution, (ii) lacks experimentally observed 3-10 helical content, and (iii) deviates strongly from average apolipophorin-III NMR structural properties. As is observed for AMBER-99SB, AMBER-03 significantly overweighs the contribution of extended and polyproline backbone configurations to the conformational equilibrium. In contrast, the AMBER-99phi force field, which was previously shown to best reproduce experimental measurements of the helix-coil transition in model helical peptides, adequately stabilizes apolipophorin-III and yields both an average gyration radius and polar solvent exposed surface area that are in excellent agreement with the NMR ensemble.