Thermodynamics of Transition Metal Ion Binding to Proteins

Modeling the thermodynamics of a transition metal (TM) ion assembly be it in proteins or in coordination complexes affords us a better understanding of the assembly and function of metalloclusters in diverse application areas including metal organic framework design, TM-based catalyst design, the trafficking of TM ions in biological systems, and drug design in metalloprotein platforms. While the structural details of TM ions bound to metalloproteins are generally well understood via experimental and computational approaches, accurate studies describing the thermodynamics of TM ion binding are rare. Herein, we demonstrate that we can obtain accurate structural and absolute binding free energies of Co2+ and Ni2+ to the enzyme glyoxalase I using an optimized 12–6–4 (m12–6–4) potential. Critically, this model simultaneously reproduces the solvation free energy of the individual TM ions and reproduces the thermodynamics of TM ion–ligand coordination as well as the thermodynamics of TM ion binding to a protein active site unlike extant models. We find the incorporation of the thermodynamics associated with protonation state changes for the TM ion (un)­binding to be crucial. The high accuracy of m12–6–4 potential in this study presents an accurate route to explore more complicated processes associated with TM cluster assembly and TM ion transport.