Improved theoretical description of protein folding kinetics from rotations in the phase space of relevant order parameters

A method is introduced to construct a better approximation for the reaction coordinate for protein folding from known order parameters. The folding of a two-state off-lattice alpha helical G (o) over bar -type protein is studied using molecular dynamics simulations. Folding times are computed directly from simulation, as well as theoretically using an equation derived by considering Brownian-type dynamics for the putative reaction coordinate. Theoretical estimates of the folding time using the number of native contacts (Q(n)) as a reaction coordinate were seen to differ quite significantly from the true folding time of the protein. By considering the properties of the bimodal free energy surface of this protein as a function of Q(n) and another relevant coordinate for folding Q (the total number of contacts), we show that by introducing a rotation in the phase space of the order parameters Q and Q(n), we can construct a new reaction coordinate q that leads to a fivefold improvement in the estimate of the folding rate. This new coordinate q, resulting from the rotation, lies along the line connecting the unfolded and folded ensemble minima of the free energy map plotted as a function of the original order parameters Q and Q(n). Possible reasons for the remaining discrepancy between the folding time computed theoretically and from folding simulations are discussed. (C) 2004 American Institute of Physics.