Ensemble Allosteric Model for the Modified Wobble Hypothesis

• Published in: The journal of physical chemistry letters Vol. 11; no. 15; pp. 6337 - 6343
• Main Authors: Sarkar, Aditya K, Sarzynska, Joanna, Lahiri, Ansuman
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.08.2020
• Subjects: Allosteric Site; Base Sequence; Codon - chemistry; Molecular Dynamics Simulation; Nucleic Acid Conformation; Physical Insights into Materials and Molecular Properties; RNA, Transfer - chemistry; Thiouridine - chemistry
• ISSN: 1948-7185; 1948-7185
• DOI: 10.1021/acs.jpclett.0c00854

The residue 2-thiouridine (s2U) provides a remarkable example for the “modified wobble” hypothesis, which postulates that some post-transcriptional modifications at the wobble position of tRNAs restrict recognition of degenerate codons. Through extensive molecular dynamics simulations using our χIDRP force field parameters, we demonstrate how this modification shifts the conformational ensemble from a predominantly disordered, as in the case of an RNA pentamer (GUUUC), to a substantially ordered population in Gs2UUUC. Our simulations clearly showed that the van der Waals interaction of sulfur played a major role in driving the disorder-to-order transition. The conformational redistribution and the slowing down of the transition between the clusters within the population in the presence of s2U suggest ensemble allostery to be a key mechanism that may play a general role in the functioning of the wobble modifications of tRNAs.