Exploring RNA destabilization mechanisms in biomolecular condensates through atomistic simulations

• 成果类型: Article
• 署名作者: Boccalini, Matteo; Berezovska, Yelyzaveta; Bussi, Giovanni; Paloni, Matteo; Barducci, Alessandro
• 署名单位: Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); International School for Advanced Studies (SISSA); University of London; University College London
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14073
• DOI: 10.1073/pnas.2425261122
• 发表日期: 2025-04-15
• 关键词: liquid phase-separation; molecular-interactions; replica exchange; force-field; protein; DYNAMICS; MODEL

摘要

Biomolecular condensates are currently recognized to play a key role in organizing cellular space and in orchestrating biochemical processes. Despite an increasing interest in characterizing their internal organization at the molecular scale, not much is known about how the densely crowded environment within these condensates affects the structural properties of recruited macromolecules. Here, we adopted explicit-solvent all-atom simulations based on a combination of enhanced sampling approaches to investigate how the conformational ensemble of an RNA hairpin is reshaped in a highly concentrated peptide solution that mimics the interior of a biomolecular condensate. Our simulations indicate that RNA structure is greatly perturbed by this distinctive physico-chemical environment, which weakens RNA secondary structure and promotes extended nonnative conformations. The resulting high-resolution picture reveals that RNA unfolding is driven by the effective solvation of nucleobases through hydrogen bonding and stacking interactions with surrounding peptides. This solvent effect can be modulated by the amino acid composition of the model condensate as proven by the differential RNA behavior observed in the case of arginine-rich and lysine-rich peptides.