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

• Published in: Biochimica et biophysica acta Vol. 1850; no. 5; pp. 996 - 1005
• Main Authors: Cazade, Pierre-André, Berezovska, Ganna, Meuwly, Markus
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2015
• Subjects: Algorithms; Cluster Analysis; hemoglobin; Hemoglobins, Abnormal - chemistry; Hemoglobins, Abnormal - metabolism; Kinetics; Ligand dynamics; Ligands; molecular dynamics; Molecular Dynamics Simulation; Monte Carlo Method; Motion; Network; Oxygen - chemistry; Oxygen - metabolism; Oxyhemoglobins - chemistry; Oxyhemoglobins - metabolism; Protein Binding; Protein Conformation; Structure-Activity Relationship; Truncated hemoglobin; Truncated Hemoglobins - chemistry; Truncated Hemoglobins - metabolism; Truncated hemoglobin; Network; Ligand dynamics
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.09.008

The nature of ligand motion in proteins is difficult to characterize directly usingexperiment. Specifically, it is unclear to what degree these motions are coupled. 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. 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. Protein and ligand dynamics are not independent from each other and ligand migration through globular proteins is not passive diffusion. 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. •Protein and ligand dynamics are coupled in globular proteins.•Transition networks are a powerful tool to analyze complex systems.•Including the protein degrees of freedom makes the networks Markovian.