Ligand escape pathways and (un)binding free energy calculations for the hexameric insulin-phenol complex.

ABSTRACT: Cooperative binding of phenolic species to insulin hexamers is known to stabilize pharmaceutical preparations of the hormone. Phenol dissociation is rapid on hexamer dissolution timescales, and phenol unbinding upon dilution is likely the first step in the conversion of (pharmaceutical) hexameric insulin to the active monomeric form upon injection. However, a clear understanding of the determinants of the rates of phenol unbinding remains obscure, chiefly because residues implicated in phenol exchange as determined by NMR are not all associated with likely unbinding routes suggested by the best-resolved hexamer structures. We apply random acceleration molecular dynamics simulation to identify potential escape routes of phenol from hydrophobic cavities in the hexameric insulin-phenol comple

SUBMITTER: Vashisth H 

PROVIDER: S-EPMC2567929 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature