title: Millisecond dynamics of RNA polymerase II translocation at atomic resolution.
abstract: Transcription is a central step in gene expression, in which the DNA template is processively read by RNA polymerase II (Pol II), synthesizing a complementary messenger RNA transcript. At each cycle, Pol II moves exactly one register along the DNA, a process known as translocation. Although X-ray crystal structures have greatly enhanced our understanding of the transcription process, the underlying molecular mechanisms of translocation remain unclear. Here we use sophisticated simulation techniques to observe Pol II translocation on a millisecond timescale and at atomistic resolution. We observe multiple cycles of forward and backward translocation and identify two previously unidentified intermediate states. We show that the bridge helix (BH) plays a key role accelerating the translocation of both the RNA:DNA hybrid and transition nucleotide by directly interacting with them. The conserved BH residues, Thr831 and Tyr836, mediate these interactions. To date, this study delivers the most detailed picture of the mechanism of Pol II translocation at atomic level.
authors.affiliation: Department of Chemistry, The Hong Kong University of Science and Technology, Kowloon, Hong Kong;
authors.forename: Daniel-Adriano
authors.initials: DA
authors.lastname: Silva
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158;
authors.forename: Dahlia R
authors.initials: DR
authors.lastname: Weiss
authors.affiliation: Department of Chemistry, The Hong Kong University of Science and Technology, Kowloon, Hong Kong;
authors.forename: Fátima
authors.initials: F
authors.lastname: Pardo Avila
authors.affiliation: Department of Chemistry, The Hong Kong University of Science and Technology, Kowloon, Hong Kong;
authors.forename: Lin-Tai
authors.initials: LT
authors.lastname: Da
authors.affiliation: Department of Structural Biology, Stanford University, Stanford, CA 94085; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Levitt
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093 xuhuihuang@ust.hk dongwang@ucsd.edu.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Chemistry, The Hong Kong University of Science and Technology, Kowloon, Hong Kong; xuhuihuang@ust.hk dongwang@ucsd.edu.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Huang
mesh_terms: D000595:Amino Acid Sequence; D008390:Markov Chains; D008956:Models, Chemical; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012319:RNA Polymerase II / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D016415:Sequence Alignment; D013997:Time Factors; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D012319:RNA Polymerase II
keywords: Markov state model; molecular dynamics; trigger loop
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