Dynamic Characterization of the Human Heme Nitric Oxide/Oxygen (HNOX) Domain under the Influence of Diatomic Gaseous Ligands

Abstract

Soluble guanylate cyclase (sGC) regulates numerous physiological processes. The β subunit Heme Nitric Oxide/Oxygen (HNOX) domain makes this protein sensitive to small gaseous ligands. The structural basis of the activation mechanism of sGC under the influence of ligands (NO, O2, CO) is poorly understood. We examine the effect of different ligands on the human sGC HNOX domain. HNOX systems with gaseous ligands were generated and explored using Molecular Dynamics (MD). The distance between heme Fe2+ and histidine in the NO-ligated HNOX (NO-HNOX) system is larger compared to the O2, CO systems. NO-HNOX rapidly adopts the conformation of the five-group metal coordination system. Loops α, β, γ and helix-f exhibit increased mobility and different hydrogen bond networks in NO-HNOX compared to the other systems. The removal of His from the Fe coordination sphere in NO-HNOX is assisted by interaction of the imidazole ring with the surrounding residues which in turn leads to the release of signaling helix-f and activation of the sGC enzyme. Insights into the conformational dynamics of a human sGC HNOX domain, especially for regions which are functionally critical for signal transduction, are valuable in the understanding of cardiovascular diseases.

Keywords

• quantum calculations
• soluble guanylate cyclase
• molecular dynamics simulations
• metal center parameter builder
• hydrogen bond occupancy
• principal component analysis