Comparative study of the folding free energy landscape of a three-strandedbeta-sheet protein with explicit and implicit solvent models

We present a molecular dynamics (MD) simulation study of the folding thermo dynamics for the three-stranded beta -sheet protein Betanova. The protein w as explicitly described by employing an all-atom model. The solvation was a ccounted for by two different solvent models: explicit TIP3P water and impl icit Generalized Born (GB) with an exterior dielectric of 80. An umbrella s ampling technique was utilized to probe thermodynamically relevant states a t different stages of folding. The generated data were combined with the we ighted histogram method to produce the two-dimensional folding free energy landscape. Sampling of conformational space was carried out in explicit sol vent at 275 K and in implicit solvent at 275, 350, and 400 K. The folding f ree energy surface of Betanova at 275 K was found to be consistent with tha t in explicit solvent. In particular, the two models agree with regard to t he location of the global minimum, the absence of a significant barrier for folding on the folding free energy surface, and the minor role of hydrogen bonding in the folding of Betanova. On the other hand the GB solvent model overestimated the stability of the protein and the folding transition temp erature. It also yielded a slightly different shape for the folding free en ergy surface, compared to the calculations with explicit solvent. Explorati on of the temperature dependence of the folding landscape in the GB solvent model yielded a similar overall shape with a shift in the global minimum t oward smaller values of the folding reaction coordinate. The inclusion of a n explicit surface-area-based treatment of hydrophobic interactions did not qualitatively change the results obtained with the GB model. We conclude t hat the GB solvent model is sufficient for studying the folding thermodynam ics of small polypeptides.