Combination of Enveloping Distribution Sampling (EDS) of a Soft-Core Reference-State Hamiltonian with One-Step Perturbation to Predict the Effect of Side Chain Substitution on the Relative Stability of Right- and Left-Helical Folds of β-Peptides.

Abstract

Folding free enthalpies of many not too different polypeptides can be efficiently and accurately predicted with the one-step perturbation (OSP) method using only one or a few molecular dynamics (MD) simulations. In this article, we introduce a combination of enveloping distribution sampling (EDS) and the OSP method (EDS-OSP) and apply it to predict the free enthalpy differences between a right-handed 2.710/12-helix and a left-handed 314-helix for 16 β-peptides with slightly different side-chain substitution patterns. An EDS simulation of a designed soft-core reference-state peptide was carried out in which both helices were sampled. Then, the soft-core atoms were perturbed into physical atoms. Thus, free enthalpy differences between the two helices for the 16 β-peptides can be predicted from only one simulation. The results predicted by EDS-OSP and a previous OSP study are very similar, i.e., the deviations between the results of the 16 peptides are mostly within the order of kBT, and the average absolute deviation is 1.2 kJ mol(-1). Together with the EDS parameter update simulation, about 128 ns of MD simulations needed to be carried out using the EDS-OSP method, while 700 ns of MD simulations were required in the previous OSP study where two separate reference-state simulations and an additional long time MD simulation of one of the 16 β-peptides were carried out. Thus, the computational effort was significantly reduced, i.e., by more than a factor of 5, using the EDS-OSP method. Hence, we consider this method an efficient tool to predict conformational free enthalpy differences from MD simulations.