Complexes of proteins with small ligands are of utmost importance in biochemistry, and therefore equilibria, formation, and decay have been investigated extensively by means of biochemical and biophysical methods. Theoretical studies of the molecular dynamics of such systems in solution are restricted to 10 ns, i.e., to fast processes. Only recently new theoretical methods have been developed not to observe the process in real time, but to explore its pathway(s) through the energy landscape. From the profiles of free energy, equilibrium and kinetic quantities can be determined using transition-state theory. This study is dedicated to the pharmacologically relevant insulin-phenol complex. The distance of the center of mass chosen as a reaction coordinate allows a reasonable description over most of the pathway. The analysis is facilitated by analytical expressions we recently derived for distance-type reaction coordinates. Only the sudden onset of rotations at the very release of the ligand cannot be parameterized by a distance. They obviously require a particular treatment. Like a preliminary study on a peptide, the present case emphasizes the contribution of internal friction inside a protein, which can be computed from simulation data. The calculated equilibrium constant and the friction-corrected rates agree well with experimental data.
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