A probabilistic approach to the effect of water hydrogen bonds on the kinetics of protein folding and protein denaturation

Previously, we presented a review of our kinetic models for the nucleation mechanism of protein folding and for the protein thermal denaturation in a barrierless way. A protein was treated as a random heteropolymer consisting of hydrophobic, hydrophilic, and neutral beads. As a crucial idea of the model, an overall potential around the cluster of native residues wherein a residue performs a chaotic motion was considered as the combination of the average dihedral, effective pairwise, and confining potentials. The overall potential as a function of the distance from the cluster has a double well shape. This allowed one to develop kinetic models for the nucleation mechanism of protein folding (NMPF) and barrierless protein denaturation (BPD) by using the mean first passage time analysis. In the original models, however, hydrogen bonding effects were taken into account only indirectly which affected the accuracy of the models because hydrogen bonding does play a crucial role in the folding, stability, and denaturation of proteins. To improve the NMPF and BPD models and explicitly take into account the hydrogen bonding “water–water” and “water–protein residue”, we have developed a probabilistic hydrogen bond (PHB) model for the effect of hydrogen bond networks of water molecules around two solute particles (immersed in water) on their interaction, and have then combined the PHB model with the NMPF and BPD models. In this paper, that can be regarded as sequel of our previous review, we analyze the modified NMPF and BPD models that explicitly take into account the effect of water–water hydrogen bonding on these processes. As expected, the application of the modified models to the folding/unfolding of two model proteins (one short, consisting of 124 residues and the other large, consisting of 2500 residues) demonstrate that the hydrogen bond networks play a very important role in the protein folding/unfolding phenomena.