Insight into a Rapid Heme Transfer Reaction between Near Transporter Domains of Staphylococcus Aureus: A Theoretical Study using QM/MM and MD Simulations

Abstract

Iron is versatile in biological systems and required cofactor in the growth and activity of all living organisms. Some gram-positive pathogens such as Staphylococcus aureus have evolved an iron-regulated surface determinant (Isd) system across its thick cell wall to steal iron from human hemoglobin and heme. Recent studies have demonstrated that heme extracted from hemoglobin is rapidly transferred into cytoplasm through NEAr Transporter (NEAT) domain of the Isd system, despite the high affinity for each domain. These observations suggest the presence of an intermediate NEAT•heme•NEAT complex. In this study, we performed restrained molecular dynamics (MD) simulations to dock the acceptor NEAT domains to the donor NEAT•heme complexes and obtained models where the two NEAT domains were arranged with two-fold pseudo symmetry around the heme molecule. The overall structures of the complex models were stably maintained during subsequent more than 900-ns unrestrained simulations. Although the hydrogen bond between a propionate group of heme and the acceptor domain was completely maintained, the hydrogen bond between the other propionate group of heme and the donor domain was broken, which may facilitate the transition of heme from the donor to the acceptor. Moreover, subsequent structural optimization using the QM/MM method showed that the two tyrosine residues, one from each NEAT domain, were simultaneously coordinated to the ferric heme iron in the intermediate complex, only if they are deprotonated. Therefore, the heme-transfer reaction proceeds by protonation on the coordinating tyrosine residue. Thus, these theoretical studies provide an atomistic insight into the intermediate structure allowing rapid heme transfer between the NEAT domains.