Coupled protein-ligand dynamics in truncated hemoglobin N from atomistic simulations and transition networks

Background: The nature of ligand motion in proteins is difficult to characterize directly usingexperiment. Specifically, it is unclear to what degree these motions are coupled. Methods: All-atom simulations are used to sample ligand motion in truncated Hemoglobin N. A transition network analysis including ligand- and protein-degrees of freedom is used to analyze the microscopic dynamics. Results: Clustering of two different subsets of MD trajectories highlights the importance of a diverse and exhaustive description to define the macrostates for a ligand-migration network. Monte Carlo simulations on the transition matrices from one particular clustering are able to faithfully capture the atomistic simulations. Contrary to clustering by ligand positions only, including a protein degree of freedom yields considerably improved coarse grained dynamics. Analysis with and without imposing detailed balance agree closely which suggests that the underlying atomistic simulations are converged with respect to sampling transitions between neighboring sites. Conclusions: Protein and ligand dynamics are not independent from each other and ligand migration through globular proteins is not passive diffusion. General significance: Transition network analysis is a powerful tool to analyze and characterize the microscopic dynamics in complex systems. This article is part of a Special Issue entitled Recent developments of molecular dynamics.