Advanced Computational Modeling of Pathways for Epigenetic Regulation and Genome Maintenance

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The project will apply cutting-edge computational modeling to advance knowledge of how chemically modified or damaged DNA is processed to ensure integrity of the genome. Despite its remarkable stability, DNA undergoes a multitude of chemical modifications in cells. These include various types of DNA damage but also regulatory modifications such as epigenetic marks. Left unchecked, DNA damage interferes with replication, potentially impairing the transmission of vital genetic information. Conversely, epigenetic marks in critical regions of the genome are essential for regulated gene expression, cell differentiation and normal development. Consequently, the biochemical pathways restoring genome integrity are intertwined with pathways that alter the epigenetic state of DNA. The project will unveil fundamental mechanisms governing the interrogation, extrusion, and coordinated processing of modified DNA bases that link DNA demethylation pathways to base excision repair. The project blends research with curriculum enrichment and student training in high performance computing and data-driven computational science, highlighted by a new project-driven course, “Computation in the Biosciences: Modeling the Machines of Life”, aligned with Georgia State University’s initiative to promote experiential learning.The research employs molecular simulation technologies, novel path optimization and enhanced sampling methodologies, large-scale supercomputing resources, and experimental analysis through collaborations to gain mechanistic insights into base excision repair and DNA demethylase enzymes. The specific goals are to: 1) uncover key principles underpinning the ability of glycosylase enzymes to select epigenetic marks or lesioned DNA bases; 2) elucidate the protein-nucleic acid interactions ensuring enzyme specificity; 3) delineate handoffs from one enzyme to the next in the pathway, which prevents accumulation of toxic intermediates. Broader impacts include knowledge that could enable modulation of enzyme activities through small molecules or rational design, as well as student training with a focus on underrepresented minority students gaining analytic and computational competencies through research and coursework.This project is jointly funded by the Genetic Mechanisms and Molecular Biophysics programs of the Molecular and Cellular Biosciences Division in the Biological Sciences Directorate.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.