Investigating the structural impacts of I64T and P311S mutations in APE1-DNA complex: a molecular dynamics approach.
Investigating the structural impacts of I64T and P311S mutations in APE1-DNA complex: a molecular dynamics approach.
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DOI：
10.1371/journal.pone.0031677
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Nagasundaram N
中科院分区：
文献类型：
--
作者：
Doss CG;Nagasundaram N
阐明蛋白质-DNA 复合物突变后的分子动态行为对于当前基因组学至关重要。分子动力学方法揭示了决定蛋白质-DNA 复合物结构和功能的变体掺入的变化。 APE1 蛋白中的有害突变会改变氨基酸的理化性质，从而影响蛋白质的稳定性和动态行为。此外，这些突变破坏了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经济有效的方法来分析与疾病易感性相关的 APE1 基因变异，并评估它们对 APE1-DNA 复合体动态行为的影响。最初，使用两种不同的计算机方法来识别 APE1 基因中的有害变异。考虑到这些方法中重叠的有害分数，并在此基础上，进一步采用 ID 为 rs61730854 (I64T) 和 rs1803120 (P311S) 的两个 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，预测的有害变异 I64T 和 P311S 会改变结构并影响 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，人类 APE1 与导致修复能力缺陷至关重要，进而导致遗传不稳定和致癌。
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.
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DOI：
10.1093/protein/12.7.549
发表时间：
1999-07-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Gromiha, MM;Oobatake, M;Sarai, A
通讯作者：
Sarai, A
影响因子：
7
作者：
Collins, FS;Brooks, LD;Chakravarti, A
通讯作者：
Chakravarti, A
影响因子：
5.6
作者：
BARLOW, DJ;THORNTON, JM
通讯作者：
THORNTON, JM
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
I-Mutant2.0：预测蛋白质序列或结构突变的稳定性变化。
影响因子：
14.9
作者：
Capriotti, E;Fariselli, P;Casadio, R
通讯作者：
Casadio, R