Title:

A Computational Model Predicting How DNMT3A Is Recruited by PRC2 to Catalyze Epigenetic Modifications Associated with the Progression of Aging

It is theorized that one of the central causes of aging is the deterioration of the epigenome [1]. The epigenetic pattern within a cell is controlled by epigenetic modifier proteins such as DNA Methyltransferase 3A (DNMT3A) and the Polycomb Repressive Complex 2 (PRC2) [2]. Previous experimental evidence indicates PRC2 physically recruits DNMT3A to specific areas throughout the genome [3]. This reported interaction is relevant to the aging process as it has been found that 90% of age dependent DNA methylation gain occurs at PRC2 target sites [4]. This suggests that the malfunction of this recruitment interaction is related to the progression of aging. The goal of this project was to develop a computational model characterizing the recruitment interaction between DNMT3A and PRC2. To do this, 3 docked models of DNMT3A and PRC2 were generated and simulated using molecular dynamics simulations. Subsequent analysis revealed that all the models seemed to be stable over time. Additionally, the experimentally reported interaction sites also appeared to be dynamically and energetically active during the simulations. This work provides a starting point to understanding the intricate recruitment interactions between large epigenetic regulatory protein complexes at an atomic level.

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