From Molecular Dynamics to Genomic Biology: Constructing Kinetic Network Models to Elucidate Transcriptional Fidelity of RNA Polymerase Ⅱ
【摘要】：Transcription, the synthesis of RNA from a complementary DNA template, plays a crucial role in cellular regulation, including differentiation, development, and other fundamental processes. In this talk, I will discuss our results on modeling the RNA polymerase Ⅱ(Pol Ⅱ, a system with ~400 K atoms) Translocation and other functional conformational changes of this enzyme at sub-millisecond timescales. We have developed a novel algorithm, Hierarchical Nystrom Extension Graph method, to construct kinetic network models to extract long timescale dynamics from short simulations. For example, we reveal that RNA polymerase Ⅱ translocation is driven purely by thermal energy and does not require the input of any additional chemical energy. Our model shows an important role for the bridge helix: Large thermal oscillations of this structural element facilitate the translocation by specific interactions that lower the free-energy barriers between four metastable states. The dynamic view of translocation presented in our study represents a substantial advance over the current understanding based on the static snapshots provided by X-ray structures of transcribing complexes. At the end of my talk, I will briefly discuss our recent progress on extending our kinetic network model to include sequence-dependent molecular dynamics of Pol Ⅱ elongation to predict transcriptional accuracy in the genome-wide transcriptomic datasets. This model creates a critical link between the structural-mechanics understanding of Pol Ⅱ fidelity and the genome-wide transcriptional accuracy.