Abstract

In vertebrates, most iron is present as heme or is chelated by proteins. Thus, Gram-positive pathogens such as Staphylococcus aureus have evolved an iron-regulated surface determinant (Isd) system that transports heme across thick cell walls into the cytoplasm. Recent studies have demonstrated that heme is rapidly transferred between the NEAr Transporter (NEAT) domains of the Isd system, despite its high affinity toward each domain, suggesting the presence of an intermediate NEAT•heme•NEAT complex. In the present study, we performed short restrained molecular dynamics (MD) simulations to dock the acceptor NEAT domain to the donor NEAT•heme complex and obtained models where the two NEAT domains were arranged with two-fold pseudo symmetry around the heme molecule. After turning off the restraints, complex structures were stably maintained during subsequent unrestrained MD simulations, except for the hydrogen bond between the propionate group of the heme molecule and the donor NEAT domain, potentially facilitating the transition of heme from the donor to the acceptor. Subsequent structural optimization using the quantum mechanics/molecular mechanics (QM/MM) method showed that two tyrosine residues, one from each NEAT domain, were simultaneously coordinated to the ferric heme iron in the intermediate complex only if they were deprotonated. Based on these results, we propose a reaction scheme for heme transfer between NEAT domains.

Highlights

  • Iron is ubiquitous in biological systems and plays various roles in the growth and activity of all living organisms

  • It is expected that IsdH-NEAT1 and -NEAT2 domains bind hemoglobin to extract heme and the NEAT3 domain receive it in a similar manner

  • Classical molecular dynamics (MD) simulations of the intermediate complex indicated that the hydrogen bond between the propionate group of heme and the donor domain was less stable than that formed with the acceptor domain, reflecting differences in heme binding affinity [14, 23, 24]

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Summary

Introduction

Iron is ubiquitous in biological systems and plays various roles in the growth and activity of all living organisms. Heme Transfer Reaction between NEAT Domains of S. aureus: QM/MM Study hemoprotein in vertebrates, pathogenic bacteria have evolved various molecular mechanisms to separate and sequester heme from hemoglobin. These mechanisms involve the transfer and degradation of heme and subsequent extraction of the iron atom. Heme transfer into S. aureus requires the expression of the iron-regulated surface determinant (Isd) proteins IsdH, IsdB, IsdA, and IsdC These proteins are anchored to the cell wall and have one or more copies of the conserved NEAr Transporter (NEAT) domain, which binds hemoglobin and performs heme transfer. Heme is subsequently transferred across the cell wall by IsdA-NEAT (IsdA-N) and IsdC-NEAT (IsdC-N) toward the membrane lipoprotein IsdE [14,15,16] ( see Fig A in S1 File)

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