Probing Extended Recognition Sites in Zn-Metalloproteins via Quantum Chemistry and Polarizable Molecular Dynamics

Abstract

Zn-metalloproteins play vital roles in numerous metabolic processes, making them high-value targets for structure-based drug design. To advance these efforts, it is useful to unravel the individual components of the intermolecular interaction energies (DE) that stabilize the Znbinding cavity, both in the absence and presence of bound protein ligands. Here, we utilize quantum chemistry (QC) to decompose DE into distinct physical contributions. The relative magnitudes of these components vary significantly depending on the coordination number (four to six) and the chemical nature ('hard'vs.'soft') of the Zn-coordinating ligands. These high-level QC analyses serve to calibrate and validate polarizable molecular mechanics potentials, effectively extending the accurate description of electronic effects beyond the immediate Zn-binding cavity to enlarged recognition sites and, ultimately, entire protein systems over long molecular dynamics (MD) simulation timescales. Following a concise overview of our QC methodology, we present validation studies on complexes containing up to 300 atoms and discuss the prospects of applying this framework to large-scale simulations of Zn-metalloprotein-ligand complexes. Finally, the structural and energetic role of discrete, highly polarizable water molecules is highlighted.