SIMULATION OF THE KINETICS OF LIGAND-BINDING TO A PROTEIN BY MOLECULAR-DYNAMICS - GEMINATE REBINDING OF NITRIC-OXIDE TO MYOGLOBIN

We have begun to use molecular dynamics to simulate the kinetics of ni tric oxide rebinding to myoglobin after photodissociation. Rebinding w as simulated using a potential function that switches smoothly between a nonbinding potential and a binding potential as a function of the p osition and orientation of the ligand, with no barrier arising from th e crossing of potential surfaces of different electron spin. In 96 of 100 trajectories, the ligand rebound in <15 ps. The kinetic progress c urve was obtained by determining the time in each trajectory at which the ligand rebound and then calculating the fraction of unbound ligand s as a function of time. The curve can be well reproduced by a simple model based on the dynamics of a Langevin particle moving on a one-dim ensional potential of mean force calculated from nonreactive protein t rajectories. The rate of escape from the energy well adjacent to the h eme is in good agreement with the value calculated from experimental d ata, suggesting that a multiple-well model provides a plausible explan ation for the nonexponential rebinding kinetics. A transition-state an alysis suggests that protein conformational relaxation coupled to the displacement of the iron from the heme plane is an unlikely cause for the nonexponential rebinding of nitric oxide.