Theoretical study of protein folding: outlining folding nuclei and estimation of protein folding rates

摘要

Our theoretical approach for prediction of folding/unfolding nuclei in threedimensional protein structures is based on a search for free energy saddle points on networks of protein unfolding pathways. Under some approximations, this search is rapidly performed by dynamic programming and results in prediction of (D values, which can be compared with those found experimentally. We show that the presented theoretical approach can be used to outline a folding nucleus in proteins' 3D structure. We demonstrate that incorporation of such 'details' as hydrogen atoms (in addition to the heavy ones) improves prediction of the folding nuclei. The model provides good predictions of folding nuclei for proteins whose 3D structures have been determined by x-ray, and is less successful for proteins whose structures have been determined by NMR. Besides, the same dynamic programming-based calculation yields the transition state free energy, and thus allows one to estimate the protein folding rate. A more direct estimate of the folding rate can be obtained from Monte Carlo simulation of refolding of known 3D protein structure, which is also described in this work. The refolding times obtained from dynamic programming and Monte Carlo simulations correlate reasonably well with logarithms of experimentally measured folding rates at mid-transition.