The transport of ligands, such as NO or O2, through internal cavities is essential for the function of globular proteins, including hemoglobin, myoglobin (Mb), neuroglobin, truncated hemoglobins, or cytoglobin. For Mb, several internal cavities (Xe1 through Xe4) were observed experimentally and they were linked to ligand storage. The present work determines barriers for xenon diffusion and relative stabilization energies for the ligand in the initial and final pocket, linking a transition depending on the occupancy state of the remaining pockets from both biased and unbiased molecular dynamics simulations. It is found that the energetics of a particular ligand migration pathway may depend on the direction in which the transition is followed and the occupancy state of the other cavities. Furthermore, the barrier height for a particular transition can depend in a non-additive fashion on the occupancy of either cavity A or B or simultaneous population of both cavities, A and B. Multiple repeats for the Xe1 → Xe2 transition reveal that the activation barrier is a distribution of barrier heights rather than one single value, which is confirmed by a distribution of transition times for the same transition from unbiased simulations. Dynamic cross correlation maps demonstrate that correlated motions occur between adjacent residues or through space, residue Phe138 is found to be a gate for the Xe1 → Xe2 transition, and the volumes of the internal cavities vary along the diffusion pathway, indicating that there is dynamic communication between the ligand and the protein. These findings suggest that Mb is an allosteric protein.
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