“Toward Computational Drug Design Against DNA G-Quadruplexes: Insights from Molecular Dynamics Simulations

Dr. Justin Lemkul is an Assistant Professor in the Department of Biochemistry at Virginia Tech. He received his B.S. and Ph.D. degrees from Virginia Tech. After completing his dissertation, he was an NIH Ruth L. Kirschstein postdoctoral fellow at the University of Maryland, Baltimore in the Department of Pharmaceutical Sciences and the Computer-Aided Drug Design Center. During this time, he developed a polarizable force field that underlies much of his current work. He returned to Virginia Tech to assume his faculty position in 2017. Dr. Lemkul’s research interests lie in structure-function relationships of biomolecules, particularly in terms of folding, misfolding, and disease. The research program in the Lemkul lab uses computational modeling and simulation approaches to understand amyloidogenic proteins, nucleic acids, and properties of small molecules toward more efficient and effective drug design against a range of chronic conditions.

G-quadruplexes (GQs) are highly ordered, noncanonical nucleic acid structures that form in guanine-rich sequences of DNA and RNA. GQs are highly enriched in promoters, origins of replication, telomeres, and 5’- and 3’-UTR of mRNA, suggesting that they function in regulating gene expression at the transcriptional and translational levels and function in genome maintenance. As such, GQs have emerged as attractive drug targets for conditions such as cancer, neurodegenerative diseases, and developmental disorders such as fragile X mental retardation. Targeting the stability of GQs with small molecules may provide the ability to modulate gene expression at the nucleic acid level rather than undertaking the conventional approach of developing drugs against protein products, which may be problematic due to mutations and nonspecific binding. Such drug design requires a detailed understanding of GQ dynamics and forces that stabilize their native states. To this end, we apply polarizable molecular dynamics simulations, which have a distinct advantage of more accurately representing critical ion interactions. This presentation will detail dynamics of three GQs in the c-KIT oncogene promoter and how their dynamics are interrelated, with specific emphasis on biophysical properties of each GQ that will impact targeted drug design.

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