Heme Proteins: The Role of Solvent on the Dynamics of Gates and Portals Revealed by MD Simulations

In the family of respiratory proteins, hemoglobins and myoglobins have been the first to be crystallized in ‘50. Despite the availability of 3D structures, issues regarding the microscopic functioning remain open, such as, for instance, the R to T switching mechanism in hemoglobin or the ligand escape process in myoglobin. Due to the relatively small number of residues, myoglobin is the suitable candidate to investigate the more general structure-function paradigm, being defined as the hydrogen atom of biology. In this work, to complement our recent study on the dynamics of internal cavities of myoglobin[1], the effect of solvation on these intrinsic pathways has been explored. In particular, 60ns-long molecular dynamics simulation of horse heart met-myoglobin was further analyzed and the dynamics of waters residing around/inside the protein with average residence times of up to tens of nanoseconds was monitored. Together with the knowledge obtained previously[1], the analysis of solvent revealed that myoglobin has in fact only few stable hydration sites in which a water molecule can stay for time longer than 2 ns. Strikingly, all of these sites are close to protein/solvent portals observed in previous studies focused on the entry/escape and migration of various ligands in myoglobin[2-4]. 1. Scorciapino, M. A.; Robertazzi, A.; Casu, M.; Ruggerone, P.; Ceccarelli, M. J. Am. Chem. Soc. 2009, 131, 11825-11832. 2. Cohen, J.; Arkhipov, A.; Braun, R.; Schulten, K. Biophys. J. 2006, 91, 1844-1857. 3. Ruscio, J. Z.; Kumar, D.; Shukla, M.; Prisant, M. G.; Murali, T. M.; Onufriev, A. V. Proc. Natl. Acad. Sci. USA 2008, 105, 9204-9209. 4. Ceccarelli, M.; Anedda, R.; Casu, M.; Ruggerone, P. Proteins 2008, 71, 1231-1236.