Role of water in the determination of protonation states of titratable residues.

Abstract

Water is the fundamental unit for living being, and its contribution in variety of crucial cellular functions is widely accepted. The presence of water molecules in protein's environment also accounts for structural optimization, in which highly conserved water molecules ensure structural stability of the biomolecule by providing protein-water (solute-solvent) hydrogen-bond interaction networks. Similarly, protonation states and pKa values of individual amino acid residues are also influenced by neighboring water molecules present in the protein's vicinity. In the present study, we have highlighted the role of water molecules in hydrogen-bond optimization, in determining pKa values and protonation states of titratable residues in JH2 domain of JAK2 apo protein. We found that inclusion or exclusion of water molecules while calculating pKa and assigning protonation states to amino acid residues during the molecular system build-up step resulted in slight differences in pKa values of few titratable residues and alternative protonation states of a certain residue. Accordingly, different protonation states of ionizable residues offer differing interaction patterns. Thus, we inferred that the presence of water optimizes the hydrogen-bond interactions by forming direct protein-water interactions and by linking via protein-protein bridging interactions. However, in the absence of water, the interaction pattern is somewhat disrupted. We assume that water molecules could modulate the plausibility of a particular protonation state of titratable residues on the basis of its fit with the local environment, by utilizing some particular hydrogen-bond contacts that would remain unexploited in the absence of water.