Exploring the energy landscape of a beta hairpin in explicit solvent.

We studied the energy landscape of the peptide Ace-GEWTYDDATKTFTVTE-Nme, taken from the C-terminal fragment (41-56) of protein G, in explicit aqueous solution by a highly parallel replica-exchange approach that combines molecular dynamics trajectories with a temperature exchange Monte Carlo process. The combined trajectories in T and configurational space allow a replica to overcome a free energy barrier present at one temperature by increasing T, changing configurations, and cooling in a self-regulated manner, thus allowing sampling of broad regions of configurational space in short (nanoseconds) time scales. The free energy landscape of this system over a wide range of temperatures shows that the system preferentially adopts a beta hairpin structure. However, the peptide also samples other stable ensembles where the peptide adopts helices and helix-turn-helix states, among others. The helical states become increasingly stable at low temperatures, but are slightly less stable than the beta turn ensemble. The energy landscape is rugged at low T, where substates are separated by large energy barriers. These barriers disappear at higher T (approximately 330 K), where the system preferentially adopts a "molten globule" state with structures similar to the beta hairpin.