Title: Polarizable Simulations of G-Quadruplexes with the Classical Drude Oscillator Model: Insights into Dynamics and Drug Design

Abstract: G-quadruplexes (GQs) are noncanonical nucleic acid structures that arise in guanine-rich stretches of DNA and RNA. These structural motifs are enriched in nucleotide sequences associated with regulating gene expression and genomic integrity, such as promoters, telomeres, and 5’-untranslated regions. As such, they serve critical roles in proper cellular function and survival and therefore may serve as novel drug targets for diseases in which targeting protein products is difficult or impossible. A challenge in these drug development efforts is the fact that most existing GQ-binding compounds rely on nonspecific, aromatic interactions that lead to poor bioavailability and specificity. Atomistic molecular dynamics (MD) simulations are a useful tool for studying the structure and dynamics of GQs. Pairwise-additive (nonpolarizable) force fields have been routinely used for decades to investigate a wide variety of biomolecules but fall short in modeling the details of nucleic acid-ion interactions, which rely strongly on induced electronic polarization. To this end, we have developed a polarizable force field based on the classical Drude oscillator model and have applied it to a range of canonical and noncanonical nucleic acids. In the context of G-quadruplexes, coordination of K+ ions is indispensable for folding structural stability. We have investigated the origin of these interactions and the specificity for K+ over other monovalent cations. Further, we have developed a computer-aided drug design workflow leveraging the insights from Drude polarizable simulations with the goal of designing compounds with high specificity for different GQs. In this presentation, I will describe the development of the Drude polarizable force field and specific outcomes of our GQ simulations regarding electrostatic properties, ion interactions, and the emergence of polarizable simulations as a critical tool in drug design targeting nucleic acids.

See more of Dr. Lemkul's research on his website: https://www.thelemkullab.com/