The Modelling And Computation Analysis Of The Soluble Guanylate Cyclase Heme Binding Domain

The soluble guanylate cyclase(sGC) catalyzing the formation ofcGMP from GTP is the predominant receptor for nitric oxide(NO) andmediator of most of its effects. sGC is a heme-containingheterodimericenzyme formed by an αsubunit and a βsubunit.Histidine 105 of the β1 subunit coordinates the heme. cGMP is animportant second messager. It can regulate so manycGMP-dependent-proteins such as: cGMP-dependent protein kinase,cGMP-dependent phosphodiesterase (PDE), cGMP-dependent ionchannel, which are involed in smooth muscle relaxation,plateletaggregation/deaggregation and neuro transmission. In the last decates,many people applied their mind to the research of the activitingmechanism of the enzyme. The revealing of this may result insignificant inflence of the therapy of cardovascular disease. However,the x-ray or NMR structure of this enzyme is still not obtained, areasonable model molecular may be the key of further research。In this paper, we carried out homology-based modelling for proteinstructure prediction of the heme binding domain used Alcaligenesxylosoxidans cytochrome c'as template, molecular dynamics (MD)simulation for structure refinement, finally we obtained a stable modelmolecular of sGC heme binding domain. Formed by similar secondaryand 3D conformation in heme binding domain gives rise to thatAlcaligenes xylosoxidans cytochrome c'sharing similar character withsGCs. However the binding site of heme is not the same according toour result. The his 105 of the molecular we modelling was on theopposite side of the original cytochrome c'template molecular used tobe, and there is a loop between 135 and 150 amino residues. Thesecondary structure prediction show that these residues were likely toform a turn formation, this may change the direction of the helix afterthe loop. Electricostatic potential computation results depict that thehelix between 150-162 amino residues and the helix between 92-114amino residues present high positive charge character and this may giverise to high repulsive interaction between two helixs. During theprocedure of dynamics the two helix above moved away to pose a stableconformation and the helix between 150-162 amino residues is morelikely to close the binding site of original cytochrome c'templatestructure and a new pocket was formed by the two helix with a positiveenvironment on the pocket surface and this may be the nature stuctureof sGC. Docking results show that there are four amino residuessignificantly involved in the heme binding. Propionic groups of theheme were close to the amino residues of Arg(139) and Tyr(112)respectively coordinating His105 residues, the opposite side of the hemewas directed to the inside of the heme pocked.. The His 158 residehappens to be on the opposite side of His 105. The distance between itand heme Fe2+ iron more likely to form a six coordinates state directlyor through a molecular water media.