Structure-Function Relationships Within the Hepatitis Delta Virus Ribozyme
| Autor: | Pavel Banáš, Nils G. Walter, Wendy Tay, Michal Otyepka, Kamali Sripathi, Jiří Šponer |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
0303 health sciences
Conformational change biology Stereochemistry Chemistry Ribozyme Biophysics Active site Protonation Crystal structure 03 medical and health sciences Crystallography 0302 clinical medicine hemic and lymphatic diseases biology.protein Structural motif Hairpin ribozyme Pseudoknot 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | ResearcherID |
| ISSN: | 0006-3495 |
| DOI: | 10.1016/j.bpj.2011.11.1530 |
| Popis: | The hepatitis delta virus (HDV) is the only known human pathogen to contain a self-cleaving catalytic RNA motif (ribozyme) in its genome. The native structure of the HDV ribozyme consists of five helices (P1 - P4 and P1.1) that come together to form a double-nested pseudoknot. The active site with the catalytically involved C75 residue lies at the heart of this complex structure. The recent emergence of a product-like crystal structure of the precursor form of the HDV ribozyme1 has cast doubt on previous structural and biochemical evidence that a significant conformational change occurs along the reaction trajectory from precursor to product. We here are using MD simulations to investigate the impact that key structural motifs as well as chemical and structural modifications necessary to crystallize the ribozyme have on conformational dynamics of the active site in this recent crystal structure. Our simulations specifically probe the effects of varying base protonation, base identity in key structural motifs, and alternate conformations of the scissile phosphate on catalytic fitness2. Analysis of our MD simulations indicates that the precise position of C75, and thus catalytic fitness, is significantly affected by the modifications introduced into the recent crystal structure. We also investigate in detail the effects of force field choice on the observed ribozyme structural dynamics, by comparing several force field variants, including our recent reparametrization of the chi profile of the Cornell et al (AMBER) force field 3. |
| Databáze: | OpenAIRE |
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