Deciphering the sequence-dependent unfolding pathways of an RNA pseudoknot with steered molecular dynamics

IF 3 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Computer-Aided Molecular Design Pub Date : 2025-04-21 DOI:10.1007/s10822-025-00598-0

Akansha Pandit, Shubham Srivastava, Neeraj Kumar, Devesh M. Sawant

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引用次数: 0

Abstract

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.

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用定向分子动力学破译RNA假结的序列依赖性展开途径

猿猴逆转录病毒1 （SRV-1）的程序性核糖体移框对RNA假结的机械特性敏感。通过展开揭示这些机械的复杂性揭示了对其结构动力学的基本见解。利用等速操纵分子动力学（CV-SMD）模拟，我们探索了假结的展开动力学和突变对展开途径的影响。除A28C外，A/U到C突变破坏环2和茎1之间的碱基三元组，显著削弱假结，使其更容易展开。除Mut5 （S2）外，茎区3个碱基对的互补突变（S1）增强了其对断裂的易感性。我们通过分析不同规范（WC）和非规范（NWC）相互作用、力扩展曲线和潜在平均力分布（作为规划突变的指导决策）的开放程度，定量评估了展开途径的变化。这些发现提供了一个量化的视角，展示了利用RNA假结的展开途径来探索RNA结构可编程性的潜力。这一见解对RNA-PROTACS和rna -适体的设计是有价值的，可以评估和操纵它们的生物折叠/展开过程。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Computer-Aided Molecular Design 生物-计算机：跨学科应用

CiteScore

8.00

自引率

8.60%

发文量

审稿时长

3 months

期刊介绍： The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.