Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
PLoS One. 2012;7(2):e31677. doi: 10.1371/journal.pone.0031677. Epub 2012 Feb 27.
Elucidating the molecular dynamic behavior of Protein-DNA complex upon mutation is crucial in current genomics. Molecular dynamics approach reveals the changes on incorporation of variants that dictate the structure and function of Protein-DNA complexes. Deleterious mutations in APE1 protein modify the physicochemical property of amino acids that affect the protein stability and dynamic behavior. Further, these mutations disrupt the binding sites and prohibit the protein to form complexes with its interacting DNA.
In this study, we developed a rapid and cost-effective method to analyze variants in APE1 gene that are associated with disease susceptibility and evaluated their impacts on APE1-DNA complex dynamic behavior. Initially, two different in silico approaches were used to identify deleterious variants in APE1 gene. Deleterious scores that overlap in these approaches were taken in concern and based on it, two nsSNPs with IDs rs61730854 (I64T) and rs1803120 (P311S) were taken further for structural analysis.
Different parameters such as RMSD, RMSF, salt bridge, H-bonds and SASA applied in Molecular dynamic study reveals that predicted deleterious variants I64T and P311S alters the structure as well as affect the stability of APE1-DNA interacting functions. This study addresses such new methods for validating functional polymorphisms of human APE1 which is critically involved in causing deficit in repair capacity, which in turn leads to genetic instability and carcinogenesis.
阐明蛋白质- DNA 复合物在突变时的分子动力学行为在当前的基因组学中至关重要。分子动力学方法揭示了变体掺入所导致的结构和功能变化，从而影响蛋白质-DNA 复合物。APE1 蛋白中的有害突变会改变氨基酸的物理化学性质，从而影响蛋白质的稳定性和动态行为。此外，这些突变会破坏结合位点，并阻止蛋白质与其相互作用的 DNA 形成复合物。
在这项研究中，我们开发了一种快速且具有成本效益的方法，用于分析与疾病易感性相关的 APE1 基因中的变体，并评估它们对 APE1-DNA 复合物动态行为的影响。最初，使用两种不同的计算方法来识别 APE1 基因中的有害变体。这些方法中重叠的有害评分受到关注，根据这些评分，进一步选择了两个具有 ID 号 rs61730854（I64T）和 rs1803120（P311S）的 nsSNP 进行结构分析。
分子动力学研究中应用的不同参数，如 RMSD、RMSF、盐桥、氢键和 SASA，表明预测的有害变体 I64T 和 P311S 不仅改变了结构，还影响了 APE1-DNA 相互作用功能的稳定性。这项研究提出了验证人类 APE1 功能多态性的新方法，因为 APE1 蛋白在修复能力缺陷中起着关键作用，这反过来又会导致遗传不稳定性和致癌作用。
