Dynamical control by water at a molecular level in protein dimer association and dissociation

Significance Despite its paramount importance, a microscopic characterization of protein association/dissociation has remained a nontrivial challenge. We have carried out atomistic simulation (biased and unbiased) to characterize insulin dimerization and dissociation process fully with a special attention to the role of water. Insulin is our system of interest because its monomer is the biologically active species but it remains in the inactive hexameric and dimeric storage forms. Our study reveals that at larger separation of two monomers (RMM ∼ 5 nm), dynamical properties of confined water molecules exhibit considerable deviation from bulklike characteristics, although structure remains bulklike. Analysis of both the large-scale water density fluctuation and protein conformational changes allows us to provide a complete picture of protein dissociation–association mechanism.