In silico evaluation of the interactions of CLOCK-BMAL۱ complex with IMPDH۲

The circadian clock is an autoregulatory system that regulates various physiological processes through the generation of approximately ۲۴-hour circadian rhythms in gene expression. The core circadian clock mechanism is mediated by a transcription/ translation-based negative feedback loop composed of CLOCK–BMAL۱ transcriptional activators. In addition to regulating of circadian gene expression, the CLOCK protein has intrinsic histone acetyltransferase activity and the ability to acetylate non-histone substrates. IMPDH۲, a critical metabolic enzyme in the de novo purine biosynthetic pathway, has been recognized as a substrate for acetylation by CLOCK. Therefore, the objective of this research is to evaluate the CLOCK and BMAL۱ interactions with IMPDH۲ at protein-protein level. By retrieving the PDB structures of the proteins, the protein-protein docking was conducted in HDOCK server. Then, the obtained docking models were visualized and analyzed in PyMOL software. The Docking Score of the best model in CLOCK-IMPDH۲ interaction was -۲۲۰.۶۴ and this result was -۲۲۳.۴۰ in BMAL۱-IMPDH۲ complex. The percentage of the charged R-chain, hydrophobic, and polar non-charged residues were ۳۵.۲, ۳۵.۲, and ۲۹.۴ in the interface of CLOCK-IMPDH۲ complex, respectively. These results were ۲۲.۸, ۴۲.۱, and ۳۵.۰۸ in the interface of BMAL۱IMPDH۲ complex, respectively. As results shown the BMAL۱ strongly binds to IMPDH۲ in comparison to CLOCK. These interactions may provide a good sca↵old for acetylation of IMPDH۲ by CLOCK-BMAL۱ complex as a post translational regulation of this enzyme. The binding of BMAL۱ to IMPDH۲ is predominantly through hydrophobic residues and this finding could be used in future research on the regulation of IMPDH۲ and drug discovery.

کلیدواژه ها:

CLOCK ، BMAL۱ ، IMPDH۲ ، Acetylation ، Protein-Protein Interactions