Title: Mechanisms of Transcription Fidelity Elucidated with Theoretical Modeling

Abstract:
We perform computer simulations of the multi-subunit RNA polymerase II (Pol II) transcription complex to study the role of an important structurally conserved element, the trigger loop, in the fidelity of transcription elongation. In particular, the effect of single point mutations of two critical residues of the trigger loop (His1085 and Leu1081) in the active site is investigated. For His1085, the mutation studies are consistent with experimental observations while the protonation work allows us to predict that the histidine must be protonated to stabilize interactions between Pol II and an incoming NTP. For Leu1081, we show that it plays an important role for both stabilizing the active site conformation and facilitating the entry of the correct matched NTP into the active site. Our results reveal the important role for the trigger loop in both substrate selection and catalysis in transcription elongation. Finally, I will also discuss our recent results on obtaining initial approximation of pathways connecting pre- and post-translocation states using a morphing algorithm.