Elucidating thermal behavior, native contacts, and folding funnels of simple lattice proteins using replica exchange Wang-Landau sampling.

Abstract

We studied the folding behavior of two coarse-grained, lattice models, the HP (hydrophobic-polar) model and the semi-flexible H0P model, whose 124 monomer long sequences were derived from the protein Ribonuclease A. Taking advantage of advanced parallel computing techniques, we applied replica exchange Wang-Landau sampling and calculated the density of states over the models entire energy ranges to high accuracy. We then determined both energetic and structural quantities in order to elucidate the folding behavior of each model completely. As a result of sufficiently long sequences and model complexity, yet computational accessibility, we were able to depict distinct free energy folding funnels for both models. In particular, we found that the HP model folds in a single-step process with a very highly degenerate native state and relatively flat low temperature folding funnel minimum. By contrast, the semi-flexible H0P model folds via a multi-step process and the native state is almost four orders of magnitude less degenerate than that for the HP model. In addition, for the H0P model, the bottom of the free energy folding funnel remains rough, even at low temperatures.