The role of hydrogen bond networks in the barrierless thermal denaturation of a native protein

Abstract

Using the mean first passage time analysis, we have recently developed a kinetic model for the thermal unfolding of a native protein in a barrierless way. A protein was considered as a random heteropolymer consisting of hydrophobic and hydrophilic beads with all the bonds and bond angles equal and constant. As a crucial idea of the model the overall potential around a folded part (cluster) of the protein in which a protein residue performs a chaotic motion was considered to be a combination of three potentials: effective pairwise, average dihedral, and confining. However, the hydrogen bonding of water molecules was not taken into account explicitly. In this paper we improve that model by combining it with a probabilistic approach to water hydrogen bonding. Thus, an additional contribution due to the disruption of hydrogen bond networks around the interacting particles (a cluster of native residues and a residue in the protein unfolded part) appears in the overall potential field around a cluster. The overall potential as a function of the distance from the cluster center has a double well shape. This allows one to determine the rates with which the cluster emits and absorbs residues by using the mean first passage time analysis. Due to a sufficiently large temperature increase or decrease, the emission rate becomes larger than the absorption rate in the whole range of cluster sizes. This leads to the unfolding of the protein in a barrierless way reminiscent of spinodal decomposition. Knowing the cluster emission and absorption rates as functions of temperature and cluster size, one can find the threshold temperatures of cold and hot barrierless denaturation as well as the corresponding unfolding times. The extended model is then applied to the unfolding of bovine pancreatic ribonuclease, consisting of 124 residues whereof 43 are hydrophobic (neutral beads are considered to be hydrophobic as well) and 81 hydrophilic.