Biomolecular Sciences Seminar Series

Dr. Dhiman Ray, University of Oregon

Title: Molecular Simulation and Artificial Intelligence to Understand RNA Conformational Dynamics and Ligand Binding

Abstract: Historically, drug discovery efforts only focused on disease causing proteins in human body. But only 1.5% of our genome is coded into proteins whereas ~70% is transcribed into non-coding RNA molecules that serve different cellular functions and contributes to diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease. However, the uniform charge density, high conformational flexibility, and lack of hydrophobic pockets makes RNA molecules difficult to target with small molecules. We use molecular dynamics simulations in combination with modern artificial intelligence (AI) techniques to study the thermodynamics, kinetics, and atomistic mechanisms of RNA conformational dynamics and ligand binding to advance our understanding of RNA targeted drug discovery. I will first describe how we established that the dynamical nature of RNA plays an essential role in facilitating small molecule ligand binding in Theophylline RNA aptamer, where we could also predict the trends of binding affinity and kinetics of natural and synthetic small molecule ligands. I will then discuss the conformational dynamics of small RNA molecules such as dinucleotides and tetranucleotides where our own AI-augmented molecular simulations strategies could correctly compute the underlying free energy surface and resolve the structures of different metastable states. Our molecular simulation approach based on statistical thermodynamics and AI provides a deep understanding of the RNA dynamics and can facilitate rational drug discovery efforts targeting RNA molecules

Host: Dr. Rajesh Nagarajan, Department of Chemistry and Biochemistry