Global optimisation by replica exchange with scaled hybrid Hamiltonians

Abstract

A global optimisation scheme based on replica-exchange molecular dynamics simulation with scaled hybrid Hamiltonians is presented and applied to fold trpzip2 peptide from extended structures with explicit water model using only eight replicas. The algorithm is shown to be capable of reproducibly optimising the peptide to structures of root mean squared deviations less than 2.5 Å with respect to all heavy atoms of NMR models. Moreover, the large amount of structural data sampled in the optimisation process enables us to provide a possible folding mechanism. The transition state ensemble is characterised by a largely formed turn and a compact packing of tryptophan 2, 4 and 9. The tryptophan 2/11 pair is found to form at a very late stage of the folding process. The first (closest to the turn) and the fourth native backbone hydrogen bonds form earlier and a picture of strict zipping up of hydrogen bonds is not observed. It is demonstrated in the present study that this global optimisation method which integrates structure prediction with approximated conformational samplings may be of help to understand the folding puzzle.