Pandit Akansha, Srivastava Shubham, Kumar Neeraj, Sawant Devesh M
Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandersindri, Kishangarh, Ajmer, Rajasthan, 305817, India.
Department of Pharmaceutical Chemistry, Bhupal Nobles' College of Pharmacy Udaipur, Udaipur, Rajasthan, India, 313001.
J Comput Aided Mol Des. 2025 Apr 21;39(1):16. doi: 10.1007/s10822-025-00598-0.
Programmed ribosomal frameshifting in Simian retrovirus-1 (SRV-1) is sensitive to the mechanical properties of an RNA pseudoknot. Unravelling these mechanical intricacies via unfolding reveals fundamental insights into their structural dynamics. Using constant velocity steered molecular dynamics (CV-SMD) simulations, we explored the unfolding dynamics and the impact of mutations on the unfolding pathway of the pseudoknot. Except for A28C, A/U to C mutations that disrupt base triples between the loop 2 and stem 1 significantly weaken the pseudoknot and make it more susceptible to unfolding. Complementary mutations in 3 base pairs of the stem region (S1) enhanced its susceptibility to disruption except for Mut5 (S2). We quantitatively assessed the variations in unfolding pathways by analysing the opening of distinct Canonical (WC) and non-canonical (NWC) interactions, force-extension curves, and potential mean force profiles (as a guiding decision for planning mutations). These findings offer a quantified perspective, showcasing the potential of utilizing the unfolding pathways of RNA pseudoknots to explore the programmability of RNA structures. This insight proves valuable for designing RNA-PROTACS and RNA-aptamers, allowing for the assessment and manipulation of their biological folding/unfolding processes.
猿猴逆转录病毒1型（SRV-1）中的程序性核糖体移码对RNA假结的机械特性敏感。通过解折叠来揭示这些机械复杂性，能深入了解其结构动力学。我们使用恒速引导分子动力学（CV-SMD）模拟，探究了假结的解折叠动力学以及突变对其解折叠途径的影响。除了A28C外，破坏环2与茎1之间碱基三联体的A/U到C突变会显著削弱假结，并使其更容易解折叠。茎区（S1）3个碱基对中的互补突变增强了其对破坏的敏感性，但Mut5（S2）除外。我们通过分析不同的标准（WC）和非标准（NWC）相互作用的打开情况、力-伸长曲线以及潜在平均力分布（作为设计突变的指导决策），定量评估了解折叠途径的变化。这些发现提供了一个量化的视角，展示了利用RNA假结的解折叠途径来探索RNA结构可编程性的潜力。这一见解对于设计RNA- PROTAC和RNA适配体很有价值，能够评估和操纵它们的生物折叠/解折叠过程。
