(362d) Simulation of the Kinetics of Protein Folding and Reassembly

We show how forward-flux sampling (FFS) can be used to study the kinetics and mechanism of structural transitions in protein systems. First, we used FFS to study the unfolding of the Trp-cage miniprotein to show that the method can be applied advantageously to elucidate the mechanism and to model the reaction coordinate in fully atomistic, water explicit simulations. Second, we studied a more complex process but in a highly coarse-grained model system: the reassembly and folding of two fragments of a split lattice protein. We found that in the fastest folding split system, a balanced distribution of the original-core amino acids (of the unsplit system) between protein fragments propitiates interchain interactions at early stages of the folding process. In the slowest folding system, the concentration of the folding nucleus in one fragment causes its early prefolding, whereas the second fragment tends to remain as a detached random coil. We also show that the reassembly rate can be either increased or decreased by tuning interchain cooperativeness via the introduction of a single point mutation that either strengthens or weakens one of the native interchain contacts (prevalent in the transition state ensemble).