Functional role of solvent entropy and conformational entropy of metal binding in dynamically-driven allostery

CAPDEVILA, DAIANA A; EDMONDS, KATHERINE A; CAMPANELLO, GREGORY; WU, HONGWEI; GONZALEZ-GUTIERREZ, GIOVANNI; GIEDROC, DAVID P.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

AMER CHEMICAL SOC

Lugar: Washington; Año: 2018

0002-7863

Allostery is a regulatory phenomenon whereby ligand binding to one site influences the binding of the same or adifferent ligand to another site on a macromolecule. The physical origins of allosteric regulation remain under intense investigation.In general terms, ligand-induced structural changes, perturbations of residue-specific dynamics, and surrounding solvent moleculesall potentially contribute to the global energetics of allostery. While the role of solvent is generally well understood in regulatoryevents associated with major protein structural rearrangements, the degree to which protein dynamics impact solvent degreesof freedom is unclear, particularly in cases of dynamically-driven allostery. With the aid of new crystal structures, extensive calorimetricand residue-specific dynamics studies over a range of timescales and temperatures, we dissect for the first time the relativedegree to which changes in solvent entropy and residue-specific dynamics impact dynamically-driven, allosteric inhibition of DNAbinding by Zn in the zinc efflux repressor, CzrA (chromosomal zinc-regulated repressor). We show that non-native residue-specificdynamics in allosterically impaired CzrA mutants are accompanied by significant perturbations in solvent entropy that cannot bepredicted from crystal structures. We conclude that functional dynamics are not necessarily restricted to protein residues, but involvesurface water molecules that may be responding to ligand (Zn)-mediated perturbations in protein internal motions that definethe conformational ensemble, rather than major structural rearrangements.