Balance between alpha and beta structures in ab initio protein folding.

Despite initial successes in folding of proteins by molecular simulation, it is becoming increasingly evident that current energy functions (force fields) tend to favor either alpha or beta secondary structure, such that the choice of force field is governed by the structural class of the protein. Here, we study the folding of peptides with either predominantly alpha (Trp cage) or beta (GB1 hairpin) structure with a modified version of the Amber ff03 force field, optimized to reproduce structural propensity in a helix-forming peptide. Using extensive replica exchange molecular dynamics simulations starting from completely unfolded configurations, we obtain the correct folded structure for each peptide, in close agreement with the experimental native structure (<1.5 A all-atom root-mean-square deviation). We obtain converged equilibrium distributions, with folded populations at standard conditions (approximately 300 K), in remarkable accord with experiment. Further comparison to experimental data from NMR spectroscopy and FRET suggests that although the folded structures are accurately reproduced, the unfolded state remains too structured and compact. Our results suggest that the backbone correction results in a force field that is transferable to the folding of proteins from different structural classes.