当前位置: X-MOL 学术J. Mol. Graph. Model. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
An integrated computational investigation to unveil the structural impacts of mutation on the InhA structural gene of Mycobacterium tuberculosis
Journal of Molecular Graphics and Modelling ( IF 2.9 ) Pub Date : 2020-09-30 , DOI: 10.1016/j.jmgm.2020.107768
Manikandan Jayaraman 1 , Krishna Ramadas 1
Affiliation  

Growing concern about the difficulty in diagnosis and treatments of drug-resistant tuberculosis falls under the major global health issues. There is an urgent need for finding novel strategies to develop drugs or bioactive molecules against the global threat of Mycobacterium tuberculosis (MTB). Isoniazid (INH) is a front line drug against tuberculosis; it primarily targets the enoyl-acyl carrier protein reductase (InhA), a potent drug target in the mycolic acid pathway of MTB. To gain deeper insight into the impact of INH resistant mutation and its influence on the structural dynamics of InhA, combined conformational dynamics and residue interaction network (RIN) studies were performed. The molecular dynamics investigation provided a hint about the structural changes altering protein activity. The principal component analysis (PCA) based free energy landscape plot highlighted the highest stable part of wild-type (WT) and mutant structures. Intriguingly, the mutation at the 78th position of InhA from its native residue valine to alanine increases the structural stability with higher NADH binding affinity. The MM-PBSA based binding energy calculations confirm that electrostatic interactions played a critical role in the binding of NADH at the binding site of InhA. The calculated binding energy score, as well as potential hydrogen bonds and salt bridge networks, proved the strong binding of mutant InhA as compared to WT. Further, the mutation potentially altered the protein network topology, thereby subsequently affected the landscape of NADH binding. The present study is an attempt to understand the structural and functional impact associated with a drug-resistant mutation (V78A) thus it will be helpful in designing potent inhibitors against drug-resistant tuberculosis.



中文翻译:

揭示突变对结核分枝杆菌InhA结构基因的结构影响的综合计算研究

对耐药性结核病诊断和治疗的困难日益引起关注,这已成为全球主要的健康问题。迫切需要寻找新的策略来开发药物或具有生物活性的分子来抵抗结核分枝杆菌的全球威胁(MTB)。异烟肼(INH)是抗结核的一线药物;它主要靶向烯酰基-酰基载体蛋白还原酶(InhA),它是MTB霉菌酸途径中的有效药物靶标。为了更深入地了解INH抗性突变的影响及其对InhA的结构动力学的影响,进行了组合的构象动力学和残基相互作用网络(RIN)研究。分子动力学研究为改变蛋白质活性的结构变化提供了提示。基于主成分分析(PCA)的自由能景观图突出显示了野生型(WT)和突变体结构的最高稳定部分。有趣的是,第78的突变InhA从其天然残基缬氨酸到丙氨酸的位置增加了结构稳定性,并具有更高的NADH结合亲和力。基于MM-PBSA的结合能计算证实,静电相互作用在InhA结合位点的NADH结合中起关键作用。计算出的结合能得分,以及潜在的氢键和盐桥网络,证明了与WT相比,突变型InhA具有很强的结合力。此外,该突变潜在地改变了蛋白质网络拓扑,从而随后影响了NADH结合的态势。本研究旨在了解与耐药突变(V78A)相关的结构和功能影响,因此将有助于设计有效的抗结核药物抑制剂。

更新日期:2020-10-06
down
wechat
bug