Cazade PA Berezovska G Meuwly M 2015 BACKGROUND The nature of ligand motion in proteins is difficult to characterize directly using experiment. 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. https://sonar.ch/global/documents/232034 eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbagen.2014.09.008 info:eu-repo/semantics/altIdentifier/pmid/25224733 Biochimica et biophysica acta. - 2015 Ligand dynamics Network Truncated hemoglobin Algorithms Cluster Analysis Hemoglobins, Abnormal Kinetics Ligands Molecular Dynamics Simulation Monte Carlo Method Motion Oxygen Oxyhemoglobins Protein Binding Protein Conformation Structure-Activity Relationship Truncated Hemoglobins Coupled protein-ligand dynamics in truncated hemoglobin N from atomistic simulations and transition networks. http://purl.org/coar/resource_type/c_6501