Uppuladinne Mallikarjunachari V N, Achalere Archana, Sonavane Uddhavesh, Joshi Rajendra
High Performance Computing - Medical and Bioinformatics Applications, Centre for Development of Advanced Computing (C-DAC) Panchavati, Pashan Pune India
RSC Adv. 2023 Aug 30;13(37):25778-25796. doi: 10.1039/d3ra03694d. eCollection 2023 Aug 29.
The tRNA, which acts as a primer for human immunodeficiency virus type 1 (HIV-1) reverse transcription, undergoes structural changes required for the formation of a primer-template complex. Small molecules have been targeted against tRNA to inhibit the primer-template complex formation. The present study aims to understand the kinetics of the conformational landscape spanned by tRNA in apo form using molecular dynamics simulations and Markov state modeling. The study is taken further to investigate the effect of small molecules like 1,4T and 1,5T on structural conformations and kinetics of tRNA, and comparative analysis is presented. Markov state modeling of tRNA apo resulted in three metastable states where the conformations have shown the non-canonical structures of the anticodon loop. Based on analyses of ligand-tRNA interactions, crucial ion and water mediated H-bonds and free energy calculations, it was observed that the 1,4-triazole more strongly binds to the tRNA compared to 1,5-triazole. However, the MSM analysis suggest that the 1,5-triazole binding to tRNA has brought rigidity not only in the binding pocket (TΨC arm, D-TΨC loop) but also in the whole structure of tRNA. This may affect the easy opening of primer tRNA required for HIV-1 reverse transcription.
转运RNA（tRNA）作为1型人类免疫缺陷病毒（HIV-1）逆转录的引物，会经历形成引物-模板复合物所需的结构变化。小分子已被作为靶向tRNA的目标，以抑制引物-模板复合物的形成。本研究旨在利用分子动力学模拟和马尔可夫状态建模来了解游离形式的tRNA所跨越的构象景观的动力学。该研究进一步探讨了1,4T和1,5T等小分子对tRNA结构构象和动力学的影响，并进行了比较分析。tRNA游离形式的马尔可夫状态建模产生了三个亚稳态，其中构象显示出反密码子环的非经典结构。基于对配体-tRNA相互作用、关键离子和水介导的氢键以及自由能计算的分析，观察到1,4-三唑比1,5-三唑更强烈地结合到tRNA上。然而，马尔可夫状态模型分析表明，1,5-三唑与tRNA的结合不仅在结合口袋（TΨC臂、D-TΨC环）中带来了刚性，而且在tRNA的整个结构中也带来了刚性。这可能会影响HIV-1逆转录所需的引物tRNA的轻松打开。
