Ligand migration in the truncated hemoglobin of Mycobacterium tuberculosis

Abstract

SummaryThe truncated hemoglobin of Mycobacterium tuberculosis (Mt-trHbO) is a small heme protein belonging to the hemoglobin superfamily. Truncated hemoglobins (trHbs) are believed to have functional roles such as terminal oxidases and oxygen sensors involved in the response to oxidative and nitrosative stress, nitric oxide (NO) detoxification, O 2 /NO chemistry, O 2 delivery under hypoxic conditions, and long-term ligand storage. Based on sequence similarities, they are classified into three groups. Experimental studies revealed that all trHbs display a 2-on-2 ahelical sandwich fold rather than the 3-on-3 a-helical sandwich fold of the classical hemoglobin fold. Using locally enhanced sampling (LESMD) molecular dynamics, the ligand-binding escape pathways from the distal heme binding cavity of MttrHbO were determined to better understand how this protein functions. The importance of specific residues, such as the group II and III invariant W(G8) residue, can be seen in terms of ligand diffusion pathways and ligand dynamics. LESMD simulations show that the wild-type Mt-trHbO has three diffusion pathways while the W(G8)F Mt-trHbO mutant has only two. The W(G8) residue plays a critical role in ligand binding and stabilization and helps regulate the rate of ligand escape from the distal heme pocket. Thus, this invariant residue is important in creating ligand diffusion pathways and possibly in the enzymatic functions of this protein.

Migration of small ligands in globins: Xe diffusion in truncated hemoglobin N

“…Therefore, ligand migration from the outside towards the active site involves ligand diffusion, often occurring through a network of connected, internal sites. Extensive research has shown that such networks of internal cavities (pockets, packing defects) exist particularly in globular proteins, and has been confirmed for heme containing proteins including myoglobin (Mb) [12–14], cytochrome b α 3 oxidase [15, 16], dimeric hemoglobin [8, 14], or truncated hemoglobins N and O [17–19]. …”

Effects of mutations on the molecular dynamics of oxygen escape from the dimeric hemoglobin of Scapharca inaequivalvis

“…Cohen and Schulten 15 used implicit ligand sampling to demonstrate different pathways in a variety of globins. Heroux, Mohan and Olsen 16 showed that a point mutation in a truncated hemoglobin could change the oxygen escape routes. In this study we apply locally enhanced sampling molecular dynamics 17 (LESMD) to visualize ligand binding in wildtype and six mutant structures of HbI.…”

Relationship among C-reactive protein, iron status, oxidative stress, and pulmonary tuberculosis

“…Cytokine can mediate and defend against pathogenic microorganisms. This situation is possibly improved, because cytokine can effectively prevent microorganisms from absorbing iron (Heroux et al, 2011). Some experts believe that mycobacteria acquire iron from the iron-binding proteins of the host's own transferrin/ferritin.…”