Features of Inorganic Ion Binding by Bovine Pancreatic Trypsin Inhibitor.

Inorganic ions play a significant role in biological systems, including their effects on protein folding, stability, and protein-protein interactions. This contribution presents an in silico study of selective ion binding by the protein bovine pancreatic trypsin inhibitor (BPTI) in NaCl(aq), KCl(aq), MgCl2(aq), and CaCl2(aq). The results were obtained within the framework of the theory of molecular liquids using the 3D-RISM (three-Dimensional Reference Interaction Site Model) approach. As established, the cation affinity to the BPTI surface decreases as Mg2+ > Ca2+ > Na+ > K+, which indicates a weakening of cation binding to the carboxylate groups of relevant residues on BPTI. The most probable locations of Na+, Mg2+ and Ca2+ were found near the carboxylate group of Glu49 on the BPTI side chain, whereas the position of K+ was between the carboxylate oxygens of Gly57 and Ala58 on the BPTI backbone. Cl- was accommodated near the hydrogens of the -NH3+ groups of Cys38 and Arg39 on the BPTI side chain. The data indicate the formation of a BPTI-Cl- contact pair and a BPTI-Mg2+ solvent-shared pair. The binding of Na+, K+, and Ca2+ to the relevant active sites of BPTI cannot be clearly attributed to direct or water-mediated binding; therefore, their binding was classified as pseudo-SIP (CIP). The obtained results do not support the prediction of the Law of Matching Water Affinity regarding the formation of stable contact pairs between kosmotropic inorganic ions and kosmotropic carboxylate groups.