Reversible peptide folding: Dependence on molecular force field used

Temperature-dependent nuclear magnetic resonance (NMR) and CD spectra of methanol solutions of a β-heptapeptide have been interpreted in such a way that the secondary structure, a 314-helix, is assumed to be stable in a temperature range of between 298 and 393 K. This is in contrast to the results of a 50-ns molecular dynamics simulation using the GROMOS96 force field, which found a melting temperature of about 340 K. This discrepancy is addressed by further computational studies using the OPLS-AA force field. The conformational energetics of N-formyl-3-aminobutanamide in vacuo are obtained using ab initio and density functional quantum-mechanical calculations at the HF/6-31G*, B3LYP/6-31G*, and B3LYP/6-311+G* levels of theory. The results permit development of torsional parameters for the OPLS-AA force field that reproduce the conformational energetics of the monomer. By varying the development procedure, three parameter sets are obtained that focus on reproducing either low-energy or high-energy conformations. These parameter sets are tested by simulating the reversible folding of the β-heptapeptide in methanol. The melting temperature of the helix formed (>360 K) is found to be higher than the one obtained from simulations using the GROMOS96 force field (∼340 K). Differences in the potential energy functions of the latter two force fields are evaluated and point to the origins of the difference in stability.