Role of Mg2+ ion in DEAD box Helicase and RNA Duplex Binding through Molecular Dynamics Simulation

Abstract

The present study comprehensively investigates the multifaceted role of Mg2+ ion in governing the activity of the DDX5 helicase enzyme, as well as its potential interaction with ATP and RNA duplexes, through an intricate exploration employing molecular dynamics (MD) simulations. DDX5, an essential member of the DEAD box helicase family, is characterized by its RecA I and RecA II domains; each domain is further categorized into distinct regions. The research delves into the molecular aspects of DDX5 by focusing on its dynamic interplay with Mg2+ ion, ATP and RNA duplexes. By utilizing state-of-the-art MD simulation assays, we characterized an indispensable function of Mg2+ ion in orchestrating ATP coordination, thereby playing a pivotal role in stabilizing the overall structure of DDX5. Most notably, the study unravels the dynamic nature of Mg2+ion's coordination geometry, which exhibits a remarkable ability to adopt both octahedral and tetrahedral arrangement. These geometries, while seemingly subtle, hold profound implications for ATP hydrolysis (a fundamental process essential for DDX5's helicase activity) and play a crucial role in maintaining DDX5's conformational integrity. The exploration of DDX5's interaction with RNA duplexes further underscores the significance of Mg2+ion. Through rigorous binding analyses, this study corroborates how the presence of Mg2+ion augments the binding propensity of RNA duplexes, inducing notable conformational shifts in DDX5's domains. Particularly noteworthy is the striking relocation of the helicase C-terminal region towards the ATP binding site, a phenomenon facilitated by Mg2+ion, which is intrinsically linked to enhance dsRNA binding. Beyond elucidating these dynamic mechanisms, the research extends its scope to the evaluation of potential inhibitors targeting DDX5's RNA binding site. In this pursuit, a promising lead molecule has been proposed, demonstrating the potential translational impact of the study's findings. In essence, this study not only advances our understanding of the intricate interplay between Mg2+ion, ATP and RNA interactions in regulating DDX5's activity but also uncovers potential avenues for therapeutic interventions. By dissecting the molecular underpinnings of DDX5's function, current study provides a firm foundation for harnessing the nuanced interconnections of these bimolecular components in modulating DDX5's role. Ultimately, these findings Role of Mg2+ ion in DEAD-box Helicase and RNA Duplex Binding through Molecular Dynamics Simulation vii Abstract illuminate both the fundamental biology of a helicase enzyme and the potential for designing targeted interventions that may leverage the delicate orchestration of Mg2+ion and its dynamic coordination geometry to manipulate DDX5's activity for therapeutic benefit.