The dynamics of t1 adenosine binding on human Argonaute 2: Understanding recognition with conformational selection

• DOI: 10.1002/pro.4377
• Publication Date: 2022-07-13T11:21:58Z
• Authors: Silvia Rinaldi; Giorgio Colombo; Antonella Paladino
• Keywords: Argonaute; Guide RNA

The control of expression in genetic regulation is a fundamental process for cell life. In RNA-mediated silencing, human Argonaute-2 protein (hAgo2) uses sequence information encoded small RNAs (guide) to identify complementary sites messenger (target) repression. specificity this molecular recognition lies at the basis mechanisms that thousands genes, which necessarily requires fine tuning complex events. Among these, binding first nucleotide target RNA (t1) emerging as an important modulator hAgo2-mediated machinery. Using atomistic dynamics-derived analyses, we address mechanism behind t1-dependent and study impact different t1 nucleotides (t1A, t1C, t1G, t1U) on conformational dynamics both hAgo2 guide-target RNAs. Only when adenine found position, directly interacts with specific pocket, favoring stabilization binding. Our findings show exploits dynamic t1-target thanks modulation conformations. Here, t1-adenine only nucleobase endowed dual mode: T-shape co-planar conformation, respectively, orthogonal parallel following base-pairs duplex. This triggers composite set interactions stabilizes distinctive ensembles. comparative analyses characteristic traits local global interplay between molecules highlight how t1A acts switch stabilization. Implications future mechanistic studies are discussed.