Exploring the molecular basis of heme hexacoordination by means of molecular dynamics simulations

LUCIANA CAPECE; LEONARDO BOECHI; ALEJANDRO D. NADRA; AXEL BIDON-CHANAL; MARCELO A. MARTI; F. JAVIER LUQUE; DARÍO A. ESTRIN

Montevideo, Uruguay

Congreso; 6th International Conference of Biological Physics - 5th Southern Cone Biophysical Congress - 34th Annual meeting of the Argentinian Biophysical Society.; 2007

Neuroglobin (Ngb) and Cytoglobin (Cyb), are two recently discovered human heme proteins. In contrast with hemoglobin or myoglobin, their heme is hexacoordinated. The function of these proteins is still unclear. Proposed functions for these proteins include oxygen transport, reactive oxygen species detoxification, hypoxia protection, and redox state sensing. For any of the proposed functions, distal histidine dissociation from the hemic iron is required. In addition, a disulfide bridge between two cysteine residues is found in both proteins and might have an important effect on the dissociation of the distal histidine. With the aim of understanding this hexa-penta coordination transition, we have performed 50ns molecular dynamics simulations in explicit water for ferrous Ngb in the hexacoordinated and pentacoordinated states. We evaluated the effect of the redox state by means of performing simulations of the protein with a disulfide bridge. We found that protein oxidation promotes a decrease in the barrier for pentacoordination and stabilizes the pentacoordinated species. The key step to obtain the pentacoordinated protein appears to be a distal histidine rotation which is concomitant with an upward displacement of the E helix. In order to compare the results for Ngb with another protein that displays an hexacoordinated heme, molecular dynamics simulations of Cyb in the reduced and oxydized forms were performed.