Computational Modeling of RNA Polymerase II Elongation Complex Dynamics

Transcription is one of the most vital processes in all living cells. To ensure that transcription works properly, the whole process is regulated at multiple levels. The complexity of the transcription regulations makes it difficult to reveal the complete mechanism of transcription. RNA polymerase II (Pol II) is the central enzyme for the transcription of all the coding genes in eukaryotes. Studies from different fields including structural biology, biochemistry, and genetics suggest that multiple proteins are involved in the transcription process and Pol II forms higher-order structures with other factors during different stages of transcription, which are initiation, elongation, and termination. Structural details of Pol II and basal elongation factors provide important insights about the elongation complexes; however, questions about the dynamics of the elongation processes and molecular mechanisms of regulation of these processes by elongation factors remain open. In this project, we aim to fill the gap between structures of elongation complexes and the molecular level of mechanisms of how these complexes form and regulate elongation by studying Pol II elongation complexes using molecular dynamics (MD) simulations. In close connection with experiments, we will computationally study the elongation stage of transcription to investigate 1) the molecular basis of the roles of elongation factors in facilitating transcription processivity, 2) the roles of elongation factors in gene-specific transcription and their relation to the neurodegenerative diseases, 3) the impacts of human disease mutations on the conformation and dynamics of the elongation complexes. MD simulations together with a variety of computational techniques including enhanced simulation methods, machine and deep learning algorithms and kinetic network models will allow us to obtain dynamics of the elongation complexes at microsecond time scales, propose mechanisms of action of the elongation factors, and investigate the defects in those mechanisms that could relate to human diseases. The successful completion of this project will have two important impacts: 1) an innovative perspective into studying large biological complexes as we will integrate advanced computational techniques to answer large-scale questions, 2) novel insights on the mechanism of transcription and its relation to human diseases as we will uncover the dynamics of these processes at the molecular level. Project Number: 1R35GM163973-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: BERCEM DUTAGACI | Institution: UNIVERSITY OF CALIFORNIA, MERCED, MERCED, CA | Award Amount: $400,910 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MBBC-A (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11329394