Quantitative Analysis of Ligand Migration from Transition Networks

In this work we use transition network analysis for the first time to investigate ligand migration in truncated hemoglobin (trHbN) and obtain kinetic information about the docking-site dynamics in the protein. A comparison with explicit water molecular dynamics simulations (100 ns in total) shows that the rate constants derived from the network analysis are realistic. The transition network analysis provides 1) The time-resolved connectivity network in the protein; 2) The half-lives of the docking sites; 3) The transition timescales between two given docking sites; and 4) The extent of population transfer among different docking sites of the protein as a function of lag time. We investigate the role of the Tyr33 and Gln58 residues in ligand migration by studying ligand migration in four mutants of trHbN. The mutation study suggests that residues Tyr33 and Gln58 stabilize the NO ligand in the Xe2 docking site of trHbN, thus facilitating the efficiency of the NO detoxification reaction.