Migration of small ligands in globins: Xe diffusion in truncated hemoglobin N

In heme proteins, the efficient transport of ligands such as NO or O2 to the binding site is achieved via ligand migration networks. A quantitative assessment of ligand diffusion in these networks is thus essential for a better understanding of the function of these proteins. For this, Xe migration in truncated hemoglobin N (trHbN) of Mycobacterium Tuberculosis was studied using molecular dynamics simulations. Transitions between pockets of the migration network and intra-pocket relaxation occur on similar time scales (10 ps and 20 ps), consistent with low free energy barriers (1-2 kcal/mol). Depending on the pocket from where Xe enters a particular transition, the conformation of the side chains lining the transition region differs which highlights the coupling between ligand and protein degrees of freedom. Furthermore, comparison of transition probabilities shows that Xe migration in trHbN is a non-Markovian process. Memory effects arise due to protein rearrangements and coupled dynamics as Xe moves through it.Author summary: Binding and transport of ligands in proteins is essential, in particular in globular proteins which often exhibit internal cavities. In truncated Hemoglobin N (trHbN) these cavities are arranged as a network with particular connectivities. The present work supports the notion that ligand diffusion in trHbN is an active process and coupled to the protein dynamics. Furthermore, transition probabilities between neighboring pockets depend on the location from where the ligand entered the transition, which is typical for non-Markovian processes. Hence, ligand migration in trHbN exhibits memory effects due to dynamical coupling between the protein and ligand motion.