Abstract
Soluble guanylate cyclase (sGC) is a key enzyme implicated in various physiological processes such as vasodilation, thrombosis and platelet aggregation. The enzyme’s Heme-Nitric oxide/Oxygen (H-NOX) binding domain is the only sensor of nitric oxide (NO) in humans, which on binding with NO activates sGC to produce the second messenger cGMP. H-NOX is thus a hot target for drug design programs. BAY60-2770 and BAY58-2667 are two widely studied activators of sGC. Here we present comparative molecular dynamics studies to understand the molecular details characterizing the binding of BAY60-2770 and BAY58-2667 with the human H-NOX (hH-NOX) and bacterial H-NOX (bH-NOX) domains. HartreeFock method was used for parametrization of both the activators. A 50 ns molecular dynamics (MD) simulation was run to identify the functionally critical regions of the H-NOX domains. The CPPTRAJ module was used for analysis. BAY60-2770 on binding with bH-NOX, triggered rotational movement in signaling helix F and significant dynamicity in loops α and β, but in hH-NOX domain the compound showed relatively lesser aforementioned structural fluctuations. Conversely, hH-NOX ligated BAY58-2667 experienced highest transitions in its helix F due to electrostatic interactions with D84, T85 and R88 residues which are not conserved in bH-NOX. These conformational transformations might be essential to communicate with downstream PAS, CC and cyclase domains of sGC. Comparative MD studies revealed that BAY bound bHNOX dynamics varied from that of hH-NOX, plausibly due to some key residues such as R40, F74 and Y112 which are not conserved in bacteria. These findings will help to the design of novel drug leads to cure diseases associated to human sGC.
Highlights
Soluble guanylate cyclase is a heterodimeric enzyme of 150 kDa molecular mass which consists of two subunits—alpha (α) and beta (β) [1]
The findings of this study suggest that dynamicity in loop β in hH-NOX is the key signal which leads to the cascade of dynamic events through loop δ and helix-F, culminating into an activated hH-NOX
The carboxylate groups of both the BAY compounds maintained similar interaction patterns with the Y-S-R motif and R116 residue of Heme-Nitric oxide/Oxygen (H-NOX) as exhibited by heme. Their ether oxygen shows a strong interaction with W74 in the bacterial H-NOX (bH-NOX) system, but this residue is not conserved in hH-NOX
Summary
Soluble guanylate cyclase is a heterodimeric enzyme of 150 kDa molecular mass which consists of two subunits—alpha (α) and beta (β) [1]. Starting from N-terminus, the β subunit folds into H-NOX, PAS, coiled coil (CC) and catalytic domains; the α subunit . Molecules 2018, 23, 2141 follows the same architecture, its N-terminal does not bind with heme and istherefore termed as pseudo-H-NOX domain [3]. The β H-NOX harbors a histidine bound heme molecule which is capable of bindingnitric oxide (NO) with femtomolar sensitivity and has been been found to bind with other gaseous ligands such as O2 and CO, though with much lesser sensitivity than that with. The sensitivity of sGC is high when its heme moiety is reduced i.e., when the heme iron is in. High concentration of cellular reactive oxygen species oxidize the heme (Fe3+ ) disabling it from capturing small gaseous ligands which in turn leads to sGC inactivation [2]. High concentration of cellular reactive oxygen species oxidize the heme (Fe3+ ) disabling it from capturing small gaseous ligands which in turn leads to sGC inactivation [2]. sGC is known as the only receptor of NO in mammals, which regulates many physiological responses such as vasodilation, smooth muscle relaxation, thrombosis, platelet aggregation and inhibition of inflammation [8,9]
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