The effect of branched side chains on the relative stability of α- and π-helices: a combination of the enveloping distribution sampling and one-step perturbation methods†

Abstract

The method of enveloping distribution sampling (EDS) to efficiently obtain free enthalpy differences between different molecular systems from a single simulation can also be used to compute free enthalpy differences between two different conformations of a system. A combination (EDS–OSP) of EDS and the one-step perturbation (OSP) method that yields many free enthalpy differences from a single simulation allows for rapid prediction of conformational free enthalpy differences for many not too different molecular systems from a single simulation. Here, we applied EDS–OSP to predict the free enthalpy differences between a π-helix and an α-helix for a set of four deca-peptides with as fifth residue Ala, Val, Leu, or Ile in aqueous solution. First, an EDS simulation of a designed soft-core reference-state Hamiltonian was carried out to sample both helices in a single simulation. Then the soft-core atoms are perturbed into real atoms of each of the four peptides. Thus, the free enthalpy differences between the π-helix and the α-helix for all four perturbed-state, real peptides can be predicted with only one simulation using EDS–OSP. EDS–OSP and the original EDS method gave very similar free enthalpy values, i.e., the average absolute deviation between the two methods for the four peptides is 0.8 kJ mol−1, while EDS–OSP required almost four times less computational effort. Side chains branched at the C β -position were found to slightly decrease the stability of the α-helical conformation with respect to the π-helical one.