De novo folding of two-helix potassium channel blockers with free-energy models and molecular dynamics

摘要

We report the predictive de novo folding of three two- helix proteins using the free-energy protein forcefield PFF01. Starting from random initial conformations 40- 90% of the members of the simulated ensembles converge to near- native conformations. The energetically lowest conformations approach the conserved part of the native conformations to within 1.64, 1.86, and 1.84 angstrom for 1WQC, 1WQD, and 1WQE, respectively. An analysis of the low- lying conformations predicts the correct topology of the disulfide bridges, which are formed in additional simulations with a constraining potential. The free energy landscapes of these proteins are very simple, suggesting them as candidates for all- atom molecular dynamics simulations. In five independent simulations we find the formation of the correct secondary structure and several folding events into the tertiary structure.