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Title: Investigation of the nucleotide triphosphate diffusion into the active site of RNA polymerase
Author: Genin, Nicolas Edmond
ISNI:       0000 0004 7657 3622
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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RNA Polymerase can be seen as a mobile molecular structure orchestrating the movement of substrate NTP and nucleic acids, regulated by some control molecules (transcription factors) and the sequential interplay of the enzyme domains. For the last 15 years, loading of rNTPs into the active site of the enzymatic complex has been regarded more or less as a settled issue. Based on the first generated crystal structures, substrates were thought to load via a pathway termed secondary channel (CH2). The latter well-accepted paradigm regarding a fundamental aspect of the transcription process is refuted and a new model, relying on overlooked structural characteristics (CH3, CH4), and accommodating a large body of pre-existing information, is presented. Important implications involve notably the fact that CH2 is mainly an exit channel, and that NTPs are selected prior to delivery into the catalytic center. Overlapping partially with the new loading hypotheses, details about substrate discrimination, error recovery and the translocation mechanism, which has been an open question in the domain for the past 20 years, are discussed. Accelerated and Steered Molecular Dynamics simulations are computed and enable to gain informative insight about the dynamics of the diffusion process. In-depth conformational and electrostatic analyses are discussed and allow gauging propensity for substrate accommodation.
Supervisor: Weinzierl, Robert Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral