Direct folding studies of various α and β strands using replica exchange molecular dynamics simulation

Abstract

Previously we presented an all-atom force field with a generalized Born solvation model (param99MOD5/GBSA) for a more balanced description of alphabeta propensities. We performed direct folding simulations on alpha helices (PDB code 2I9M and 1WN8), beta hairpins (15beta peptide and PDB code 1E0Q), and beta-sheet peptide ((D)P(D)P-II) to investigate the transferability of a new param99MOD5/GBSA force field. For direct folding simulations, we used the replica exchange molecular dynamics simulation starting with a fully extended conformer. In the converged free energy landscapes for all five peptides, each of the lowest free energy predicted structures closely matched the corresponding NMR native structure within a backbone rmsd value of 2.0 A at experimental temperatures. The thermal denaturation profiles of all the peptides fit a two-state model well, giving several key thermodynamic parameters for comparison. Especially for 15beta and (D)P(D)P-II whose thermodynamic data were available from the experiment, our simulated thermodynamic quantities agree reasonably well with the experiment. In this work, we demonstrate that the modified force field successfully differentiates native structures of alpha and beta strands under the global free energy minimum condition, so that it can be used in ab initio folding simulations for more complex motifs.