Assessing the structural dynamics of the glucose-6-phosphate dehydrogenase dimer interface using molecular dynamics simulation and ligand screening using computer aided drug discovery
Naveen Eugene Louis, Muaawia Ahmed Hamza, Puteri Nur Sarah Diana Engku Baharuddin, Shamini Chandran, Nurriza Ab Latif, Mona Awad Alonazi, Joazaizulfazli Jamalis, Arjumand Warsy, Syazwani Itri Amran
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引用次数: 0
Abstract
ABSTRACTGlucose-6-phosphate-dehydrogenase deficiency is the most common enzymopathy. Current therapies for G6PD deficiency are unable to treat a broad range of pathogenic variants. In this study, we assess the structural dynamics of six G6PD variants using molecular dynamics simulation to correlate their genotypic and phenotypic attributes. G6PD multimerisation is highly influenced by its ligands G6P and NADP, where the former disrupts dimer formation, and the latter facilitates tetramerisation. Results of our simulation demonstrate that the WT and a relatively stable variant (G131V), were found to have greater NADP binding occupancy and hydrogen bonds between βN sheet of each monomeric subunit, thereby increasing the stability of the dimer interface. G6PD protein structures with high structural integrity at the dimer interface were found to be compact, characterised by low radius of gyration values, and increased surface area or high solvent-accessible surface area at the tetramer salt bridge residues. Using mutational clustering methods, a critical G6PD region at the βK–βL loop was identified and may serve as a potential target for treatment. We further extend this study to identify chemical compounds that induce modulatory effects on the protein using computer aided drug discovery which warrant further studies and future testing.KEYWORDS: Glucose-6-phosphate-dehydrogenase deficiencyprotein multimerisationmolecular dynamics simulationcomputer aided drug discoverymolecular docking Disclosure statementNo potential conflict of interest was reported by the author(s).Additional informationFundingThis work was supported by the Fundamental Research Grant Scheme (FRGS) from the Malaysian Ministry of Higher Education (MoHE) under grant number FRGS/1/2019/SKK08/UTM/02/1 awarded to Dr Syazwani Itri Amran. This work was also supported by the Intramural Research Fund under grant number 4B363 from the Ministry of Health, Kingdom of Saudi Arabia awarded to Dr Muaawia Ahmed Hamza. We also acknowledge support from University of Technology Malaysia (UTM) under grant number 15J90. We thank Dr Goh Kian Mau for assistance through intellectual discussions about the project.
期刊介绍:
Molecular Simulation covers all aspects of research related to, or of importance to, molecular modelling and simulation.
Molecular Simulation brings together the most significant papers concerned with applications of simulation methods, and original contributions to the development of simulation methodology from biology, biochemistry, chemistry, engineering, materials science, medicine and physics.
The aim is to provide a forum in which cross fertilization between application areas, methodologies, disciplines, as well as academic and industrial researchers can take place and new developments can be encouraged.
Molecular Simulation is of interest to all researchers using or developing simulation methods based on statistical mechanics/quantum mechanics. This includes molecular dynamics (MD, AIMD), Monte Carlo, ab initio methods related to simulation, multiscale and coarse graining methods.