基于结构的肾素-血管紧张素原复合物中单核苷酸变异分析。
Structure-Based Analysis of Single Nucleotide Variants in the Renin-Angiotensinogen Complex.
机构信息
Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa.
Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa.
出版信息
Glob Heart. 2017 Jun;12(2):121-132. doi: 10.1016/j.gheart.2017.01.006. Epub 2017 Mar 13.
BACKGROUND
The renin-angiotensin system (RAS) plays an important role in regulating blood pressure and controlling sodium levels in the blood. Hyperactivity of this system has been linked to numerous conditions including hypertension, kidney disease, and congestive heart failure. Three classes of drugs have been developed to inhibit RAS. In this study, we provide a structure-based analysis of the effect of single nucleotide variants (SNVs) on the interaction between renin and angiotensinogen with the aim of revealing important residues and potentially damaging variants for further inhibitor design purposes.
OBJECTIVES
To identify SNVs that have functional and potentially damaging effects on the renin-angiotensinogen complex and to use computational approaches to investigate how SNVs might have damaging effects.
METHODS
A comprehensive set of all known SNVs in the renin and angiotensinogen proteins was extracted from the HUMA database. This dataset was filtered by removing synonymous and missense variants and using the VAPOR pipeline to predict which variants were likely to be deleterious. Variants in the filtered dataset were modeled into the renin-angiotensinogen complex using MODELLER and subjected to molecular dynamics simulations using GROMACS. The residue interaction networks of the resultant trajectories were analyzed using graph theory.
CONCLUSIONS
This research identified important SNVs in the interface of RAS and showed how they might affect the function of the proteins. For instance, the mutant complex containing the variant P40L in angiotensinogen caused instability in the complex, indicating that this mutation plays an important role in disrupting the interaction between renin and angiotensinogen. The mutant complex containing the SNV A188V in renin was shown to have significantly increased fluctuation in the residue interaction networks. D104N in renin, associated with renal tubular dysgenesis, caused increased rigidity in the protein complex comparison to the wild type, which probably in turn negatively affects the function of RAS.
背景
肾素-血管紧张素系统（RAS）在调节血压和控制血液中的钠水平方面起着重要作用。该系统的过度活跃与许多疾病有关，包括高血压、肾病和充血性心力衰竭。已经开发出三类药物来抑制 RAS。在这项研究中，我们提供了基于结构的分析，研究单核苷酸变异（SNV）对肾素和血管紧张素原之间相互作用的影响，目的是揭示重要的残基和潜在的破坏性变异，以进一步设计抑制剂。
目的
确定对肾素-血管紧张素原复合物具有功能和潜在破坏性影响的 SNV，并使用计算方法研究 SNV 如何产生破坏性影响。
方法
从 HUMA 数据库中提取了肾素和血管紧张素原蛋白中所有已知的 SNV 的综合数据集。通过去除同义突变和错义突变，并使用 VAPOR 管道来预测哪些变体可能具有破坏性，对数据集进行过滤。使用 MODELLER 将过滤后的数据集中的变体建模到肾素-血管紧张素原复合物中，并使用 GROMACS 对其进行分子动力学模拟。使用图论分析所得轨迹的残基相互作用网络。
结论
这项研究确定了 RAS 界面中的重要 SNV，并展示了它们如何影响蛋白质的功能。例如，血管紧张素原中含有 P40L 突变的突变体复合物导致复合物不稳定，表明该突变在破坏肾素和血管紧张素原之间的相互作用方面起着重要作用。肾素中含有 SNV A188V 的突变体复合物显示出残基相互作用网络的显著增加波动。肾素中的 D104N 与肾小管发育不全有关，与野生型相比，使蛋白复合物的刚性增加，这可能反过来对 RAS 的功能产生负面影响。
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