Assessing the structural dynamics of the glucose-6-phosphate dehydrogenase dimer interface using molecular dynamics simulation and ligand screening using computer aided drug discovery

IF 1.9 4区 化学 Q4 CHEMISTRY, PHYSICAL Molecular Simulation Pub Date : 2023-11-01 DOI:10.1080/08927022.2023.2274871
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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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.
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利用分子动力学模拟和计算机辅助药物发现的配体筛选评估葡萄糖-6-磷酸脱氢酶二聚体界面的结构动力学
葡萄糖-6-磷酸脱氢酶缺乏症是最常见的酶病。目前针对G6PD缺乏症的治疗方法无法治疗广泛的致病变异。在这项研究中,我们使用分子动力学模拟来评估6种G6PD变异的结构动力学,以关联它们的基因型和表型属性。G6PD的聚合受到其配体G6P和NADP的高度影响,前者破坏二聚体的形成,后者促进四聚体的形成。我们的模拟结果表明,WT和相对稳定的变体(G131V)被发现具有更大的NADP结合占用率和每个单体亚基βN片之间的氢键,从而增加了二聚体界面的稳定性。在二聚体界面处具有高结构完整性的G6PD蛋白结构紧凑,具有低旋转半径值的特点,并且在四聚体盐桥残基处增加表面积或高溶剂可及表面积。利用突变聚类方法,在βK -βL环上发现了一个关键的G6PD区域,可能是治疗的潜在靶点。我们进一步扩展了这项研究,利用计算机辅助药物发现来识别诱导蛋白质调节作用的化合物,这需要进一步的研究和未来的测试。关键词:葡萄糖-6-磷酸脱氢酶缺陷蛋白多聚分子动力学模拟计算机辅助药物发现分子对接披露声明作者未报告潜在利益冲突。本研究得到马来西亚高等教育部(MoHE)基础研究资助计划(FRGS)的支持,资助号为FRGS/1/2019/SKK08/UTM/02/1,授予Syazwani Itri Amran博士。这项工作还得到了校内研究基金的支持,赠款编号为4B363,由沙特阿拉伯王国卫生部授予muawia Ahmed Hamza博士。我们也感谢马来西亚科技大学(UTM)的资助,资助号为15J90。我们感谢吴建茂博士通过对项目的理智讨论提供的帮助。
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来源期刊
Molecular Simulation
Molecular Simulation 化学-物理:原子、分子和化学物理
CiteScore
3.80
自引率
9.50%
发文量
128
审稿时长
3.1 months
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.
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