Devi Chandra, Ranjan Prashant, Raj Sonam, Das Parimal
Centre for Genetic Disorders, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh 221005 India.
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.
3 Biotech. 2024 Sep;14(9):211. doi: 10.1007/s13205-024-04057-9. Epub 2024 Aug 24.
We analyzed the impact of nine previously identified missense variants from our studies, including c.6928G > A p.G2310R, c.8809G > A p.E2937K, c.2899 T > C p.W967R, c.6284A > G p.D2095G, c.6644G > A p.R2215Q, c.7810G > A p.D2604N, c.11249G > C p.R3750P, c.1001C > T p.T334M, and c.3101A > G p.N1034S on RNA structures and PC1 protein structure dynamics utilizing computational tools. RNA structure analysis was done using short RNA snippets of 41 nucleotides with the variant position at the 21st nucleotide, ensuring 20 bases on both sides. The secondary structures of these RNA snippets were predicted using RNAstructure. Structural changes of the mutants compared to the wild type were analyzed using the MutaRNA webserver. Molecular dynamics (MD) simulation of PC1 wild-type and mutant protein regions were performed using GROMACS 2018 (GROMOS96 54a7 force field). Findings revealed that five variants including c.8809G > A (p.E2937K), c.11249G > C (p.R3750P), c.3101A > G (p.N1034S), c.6928G > A (p.G2310R), c.6644G > A (p.R2215Q) exhibited major alterations in RNA structures and thereby their interactions with other proteins or RNAs affecting protein structure dynamics. While certain variants have minimal impact on RNA conformations, their observed alterations in MD simulations indicate impact on protein structure dynamics highlighting the importance of evaluating the functional consequences of genetic variants by considering both RNA and protein levels. The study also emphasizes that each missense variant exerts a unique impact on RNA stability, and protein structure dynamics, potentially contributing to the heterogeneous clinical manifestations and progression observed in Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients offering a novel perspective in this direction. Thus, the utility of studying the structure dynamics through computational tools can help in prioritizing the variants for their functional implications, understanding the molecular mechanisms underlying variability in ADPKD presentation and developing targeted therapeutic interventions.
The online version contains supplementary material available at 10.1007/s13205-024-04057-9.
我们分析了我们研究中先前鉴定的9个错义变体的影响，包括c.6928G＞A p.G2310R、c.8809G＞A p.E2937K、c.2899T＞C p.W967R、c.6284A＞G p.D2095G、c.6644G＞A p.R2215Q、c.7810G＞A p.D2604N、c.11249G＞C p.R3750P、c.1001C＞T p.T334M和c.3101A＞G p.N1034S对RNA结构和PC1蛋白质结构动力学的影响，利用计算工具进行分析。RNA结构分析使用41个核苷酸的短RNA片段，变异位点位于第21个核苷酸处，确保两侧各有20个碱基。使用RNAstructure预测这些RNA片段的二级结构。使用MutaRNA网络服务器分析突变体与野生型相比的结构变化。使用GROMACS 2018（GROMOS96 54a7力场）对PC1野生型和突变型蛋白质区域进行分子动力学（MD）模拟。研究结果显示，包括c.8809G＞A（p.E2937K）、c.11249G＞C（p.R3750P）、c.3101A＞G（p.N1034S）、c.6928G＞A（p.G2310R）、c.6644G＞A（p.R2215Q）在内的5个变体在RNA结构中表现出主要改变，从而影响它们与其他蛋白质或RNA的相互作用，进而影响蛋白质结构动力学。虽然某些变体对RNA构象影响最小，但在MD模拟中观察到的它们的改变表明对蛋白质结构动力学有影响，突出了通过考虑RNA和蛋白质水平来评估基因变体功能后果的重要性。该研究还强调，每个错义变体对RNA稳定性和蛋白质结构动力学都有独特影响，可能导致常染色体显性多囊肾病（ADPKD）患者出现异质性临床表现和病情进展，在这一方向上提供了新的视角。因此，通过计算工具研究结构动力学的实用性有助于根据变体的功能影响对其进行优先级排序，理解ADPKD表现变异性的分子机制，并开发针对性的治疗干预措施。
在线版本包含可在10.1007/s13205-024-04057-9获取的补充材料。
