我们分析了我们研究中先前鉴定的9个错义PKD1变体的影响,包括c.6928G>Ap.G2310R,c.8809G>Ap.E2937K,c.2899T>Cp.W967R,c.6284A>Gp.D2095G,c.664G>Ap.R2215Q,c.7810G>Ap.D2604N,c.11249G>Cp.R3750P,c.1001C>Tp.T334M,和c.3101A>Gp.N1034S关于RNA结构和PC1蛋白质结构动力学的计算工具。使用41个核苷酸的短RNA片段进行RNA结构分析,变体位置在第21个核苷酸,确保双方有20个基地。使用RNA结构预测这些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GROMACS2018(GROMOS9654a7力场)进行PC1野生型和突变蛋白区域的分子动力学(MD)模拟。研究结果表明,五种变体包括c.8809G>A(p。E2937K),c.11249G>C(p。R3750P),C.3101A>G(p。N1034S),c.6928G>A(p。G2310R),c.664G>A(p。R2215Q)表现出RNA结构的主要变化,从而与其他蛋白质或RNA的相互作用影响蛋白质结构动力学。虽然某些变体对RNA构象的影响很小,他们在MD模拟中观察到的变化表明对蛋白质结构动力学的影响,突出了通过考虑RNA和蛋白质水平来评估遗传变异的功能后果的重要性。该研究还强调,每个错义变体对RNA稳定性都有独特的影响。和蛋白质结构动力学,在常染色体显性多囊肾病(ADPKD)患者中观察到的异质性临床表现和进展可能是重要原因,为这一方向提供了新的观点。因此,通过计算工具研究结构动力学的效用可以帮助优先考虑变体的功能含义,了解ADPKD表现变异性的分子机制,并制定有针对性的治疗干预措施。
■在线版本包含补充材料,可在10.1007/s13205-024-04057-9获得。
We analyzed the impact of nine previously identified missense PKD1 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.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13205-024-04057-9.