Influence of variation of a side chain on the folding equilibrium of a β-peptide: limitations of one-step perturbation.

In a recent study (Lin et al., Helv. Chim. Acta 2011, 94, 597), the one-step perturbation method was applied to tackle a challenging computational problem, that is, the calculation of the folding free enthalpies ΔGF,U of six hepta-β-peptides with different, Ala, Val, Leu, Ile, Ser, or Thr, side chains in the fifth residue. The ΔGF,U values obtained using one-step perturbation based on a single molecular dynamics simulation of a judiciously chosen reference state with soft-core atoms in the side chain of the fifth residue showed an overall accuracy of about kB T for the four peptides with nonpolar side chains, but twice as large deviations were observed for the peptides with polar side chains. Here, alternative reference-state Hamiltonians that better cover the conformational space relevant to these peptides are investigated, and post simulation rotational sampling of the χ1 and χ2 torsional angles of the fifth residue is carried out to sample different orientations of the side chain. A reference state with rather soft atoms yields accurate ΔGF,U values for the peptides with the Ser and Thr side chains, but it failed to correctly predict the folding free enthalpy for one peptide with a nonpolar side chain, that is, Leu. Based on the results and those of earlier studies, possible ways to improve the accuracy of the efficient one-step perturbation technique to compute free enthalpies of folding are discussed.