a Molecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology , Tezpur University , Tezpur , India.
J Biomol Struct Dyn. 2019 Aug;37(13):3322-3336. doi: 10.1080/07391102.2018.1517051. Epub 2018 Dec 5.
The complementation group A (XPA) protein functions as a primary damage verifier and as a scaffold protein in nucleotide excision repair (NER) in all higher organisms. New evidence of XPA's existence as a dimer and the redefinition of its DNA-binding domain (DBD) raises new questions regarding the stability and functional position of XPA in NER. Here, we have investigated XPA's dimeric status with respect to its previously defined DBD (XPA) as well as with its redefined DBD (XPA). We studied the stability of XPA and XPA homo-dimer systems using all-atom molecular dynamics simulation, and we have also characterized the protein-protein interactions (PPI) of these two homo-dimeric forms of XPA. After conducting the root mean square deviation (RMSD) analyses, it was observed that the XPA homo-dimer has better stability than XPA. It was also found that XPA has a larger number of hydrogen bonds, salt bridges, and hydrophobic interactions than the XPA homo-dimer. We further found that Lys, Glu, Gln, Asn, and Arg residues shared the major contribution toward the intermolecular interactions in XPA homo-dimers. The binding free energy (BFE) analysis, which used the molecular mechanics Poisson-Boltzmann method (MM-PBSA) and the generalized Born and surface area continuum solvation model (GBSA) for both XPA homo-dimers, also substantiated the positive result in favor of the stability of the XPA homo-dimer. Communicated by Ramaswamy H. Sarma.
补体成分 A（XPA）蛋白在所有高等生物中作为核苷酸切除修复（NER）的主要损伤验证者和支架蛋白发挥作用。XPA 作为二聚体存在的新证据及其 DNA 结合域（DBD）的重新定义，引发了关于 XPA 在 NER 中的稳定性和功能位置的新问题。在这里，我们研究了 XPA 的二聚体状态，分别针对其先前定义的 DBD（XPA）和重新定义的 DBD（XPA）。我们使用全原子分子动力学模拟研究了 XPA 和 XPA 同源二聚体系统的稳定性，并对这两种 XPA 同源二聚体形式的蛋白质-蛋白质相互作用（PPI）进行了表征。在进行均方根偏差（RMSD）分析后，观察到 XPA 同源二聚体比 XPA 更稳定。还发现 XPA 比 XPA 同源二聚体具有更多的氢键、盐桥和疏水相互作用。我们进一步发现，Lys、Glu、Gln、Asn 和 Arg 残基在 XPA 同源二聚体的分子间相互作用中起主要作用。使用分子力学泊松-玻尔兹曼方法（MM-PBSA）和广义 Born 和表面积连续体溶剂化模型（GBSA）对两种 XPA 同源二聚体进行的结合自由能（BFE）分析也证实了 XPA 同源二聚体稳定性的积极结果。由 Ramaswamy H. Sarma 传达。
