Influence of Cataract Causing Mutations on αA-Crystallin: A Computational Approach

IF 1.9 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY The Protein Journal Pub Date : 2024-11-01 DOI:10.1007/s10930-024-10239-4
Kajal Abrol, Jayarani Basumatari, Jupita Handique, Muthukumaran Rajagopalan, Amutha Ramaswamy
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Abstract

The αA-crystallin protein plays a vital role in maintaining the refractive index and transparency of the eye lens. Significant clinical studies have emerged as the αA-crystallin is prone to aggregation, resulting in the formation of cataracts with varied etiologies due to mutations. This work aims to comprehend the structural and functional role of cataract-causing mutations in αA-crystallin, particularly at N-Terminal and α-Crystallin Domains, using in-silico approaches including molecular dynamics simulation. About 19 mutants of αA-crystallin along with native structure were simulated for 100 ns and the post-simulations analyses reveal pronounced dynamics of αA-crystallin due to the enhanced structure flexibility as its native compactness was lost and is witnessed mainly by the mutants R12L, R21L, R21Q, R54L, R65Q, R116C and R116H. It is observed that αA-crystallin discloses the NTD motions as the dominant one and the same was endorsed by the linear variation between Rg and the center-of-mass of αA-crystallin. Interestingly, such enhanced dynamics of αA-crystallin mutants associated with the structure flexibility is internally modulated by the dynamic exchange of secondary structure elements β-sheets and coils (R2 = 0.619) during simulation. Besides, the observed pronounced dynamics of dimer interface region (β3-L6-β4 segment) of ACD along with CTD dynamics also gains importance. Particularly, the highly dynamic mutants are also characterized by enhanced non-covalent and hydrophobic interactions which renders detrimental effects towards its stability, and favours possible protein unfolding mechanisms. Overall, this study highlights the mutation-mediated structural distortions in αA-crystallin and demands the need for further potential development of inhibitors against cataract formation.

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导致白内障的突变对αA-结晶素的影响:计算方法
αA-晶体蛋白在维持眼睛晶状体的折射率和透明度方面发挥着重要作用。由于αA-晶体蛋白容易发生聚集,从而导致不同病因的突变形成白内障,因此出现了重要的临床研究。这项研究旨在利用分子动力学模拟等室内方法,理解导致白内障的αA-结晶素突变的结构和功能作用,特别是在N端和α-结晶素域。我们对αA-结晶素的大约 19 个突变体和原生结构进行了 100 ns 的模拟,模拟后的分析表明,由于αA-结晶素失去了原生结构的紧密性,结构灵活性增强,因此αA-结晶素具有明显的动态变化,这主要体现在突变体 R12L、R21L、R21Q、R54L、R65Q、R116C 和 R116H 上。据观察,αA-结晶素以 NTD 运动为主,Rg 与αA-结晶素质量中心之间的线性变化也证明了这一点。有趣的是,αA-结晶素突变体与结构灵活性相关的动态增强在模拟过程中受到二级结构元素β片和线圈动态交换(R2 = 0.619)的内部调节。此外,观察到的 ACD 的二聚体界面区(β3-L6-β4 段)的明显动态以及 CTD 动态也变得非常重要。特别是,高动态突变体还具有非共价和疏水相互作用增强的特点,这对其稳定性产生了不利影响,并有利于可能的蛋白质折叠机制。总之,这项研究强调了突变介导的αA-结晶蛋白结构畸变,并要求进一步开发潜在的白内障形成抑制剂。
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来源期刊
The Protein Journal
The Protein Journal 生物-生化与分子生物学
CiteScore
5.20
自引率
0.00%
发文量
57
审稿时长
12 months
期刊介绍: The Protein Journal (formerly the Journal of Protein Chemistry) publishes original research work on all aspects of proteins and peptides. These include studies concerned with covalent or three-dimensional structure determination (X-ray, NMR, cryoEM, EPR/ESR, optical methods, etc.), computational aspects of protein structure and function, protein folding and misfolding, assembly, genetics, evolution, proteomics, molecular biology, protein engineering, protein nanotechnology, protein purification and analysis and peptide synthesis, as well as the elucidation and interpretation of the molecular bases of biological activities of proteins and peptides. We accept original research papers, reviews, mini-reviews, hypotheses, opinion papers, and letters to the editor.
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