Folding Trp-cage to atomic resolution: Searching parameter space for a free-energy minimum

COMP 180

Olgun Guvench, and Charles L. Brooks III. Department of Molecular Biology, TPC6, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037
We present an all-atom implicit-water protein force-field and its parameterization using a self-consistent approach, with the target of parameterization being the folding of the 20-residue mini-protein Trp-cage. The force-field includes interaction terms that are all short-ranged in nature, making it computationally expedient. The terms accounting for intramolecular and protein water hydrogen bonding, as well as the hydrophobic effect, are all of the form k*f(x,) where f(x) is a function of the atomic coordinates and k is an energetic parameter subject to optimization. Using a self-consistent Z-score optimization protocol in conjunction with replica-exchange molecular dynamics (REMD) for enhanced thermodynamic sampling, we show that it is possible to start with a set of parameters (k's) that lead to rapid denaturation of the protein at laboratory temperature and to algorithmically optimize these parameters such the native state becomes a 2 kcal/mol free-energy minimum at laboratory temperature.