Dynamic simulations of oxygen binding to myoglobin.

We report dynamic simulations of the process by which a dioxygen molecule enters or leaves the heme pocket region of myoglobin along a path between the distal histidine (E7) and valine (E11). Our reaction coordinate measures the distance of the ligand from a "dividing plane" defined by three protein atoms. The equilibrium probability distribution as a function of this coordinate is determined by a series of molecular-dynamic simulations with overlapping "umbrella" constraining potentials; the resulting potential of mean force has a barrier of about 7 kcal/mol for exit from the heme pocket. A comparison of this free energy profile with the corresponding potential energy profile suggests that entropy effects dominate the kinetic barrier. Reactive trajectories are generated from dynamic simulations beginning at the top of the potential of mean force; only a small fraction of these recross the dividing surface, indicating that transition state theory may be a good approximation for this process.