Advanced Computational Modeling of Pathways for Epigenetic Regulation and Genome Maintenance

该项目将应用尖端的计算模型来提高对化学修饰或损坏的DNA是如何处理的知识，以确保基因组的完整性。尽管DNA非常稳定，但它在细胞中经历了大量的化学修饰。这些包括各种类型的DNA损伤，但也包括监管修改，如表观遗传标记。如果不加以控制，DNA损伤会干扰复制，可能会损害重要遗传信息的传输。相反，基因组关键区域的表观遗传标记对于调控基因表达、细胞分化和正常发育是必不可少的。因此，恢复基因组完整性的生化途径与改变DNA表观遗传状态的途径交织在一起。该项目将揭示控制DNA碱基的询问、挤出和协调处理的基本机制，这些DNA碱基将DNA去甲基化途径与碱基切除修复联系起来。该项目将高性能计算和数据驱动计算科学方面的研究与课程丰富和学生培训结合在一起，重点是一门新的项目驱动课程--《生物科学中的计算：生命机器的建模》，该课程与佐治亚州立大学促进体验式学习的倡议保持一致。研究采用分子模拟技术、新颖的路径优化和增强的采样方法、大规模超级计算资源，以及通过合作进行实验分析，以获得对碱基切除修复和DNA去甲基酶的机械性见解。具体目标是：1)揭示支持糖基酶选择表观遗传标记或受损DNA碱基能力的关键原理；2)阐明确保酶特异性的蛋白质-核酸相互作用；3)描述在该途径中从一个酶到下一个酶的切换，以防止有毒中间体的积累。更广泛的影响包括能够通过小分子或合理设计来调节酶活性的知识，以及学生培训，重点是未被充分代表的少数族裔学生通过研究和课程获得分析和计算能力。该项目由生物科学理事会分子和细胞生物科学部的遗传机制和分子生物物理学项目共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.