Chemical Feasibility of the General Acid/Base Mechanism of glmS Ribozyme Self-Cleavage

0447582 - BFÚ 2016 RIV US eng J - Journal Article
Dubecký, M. - Walter, Nils G. - Šponer, Jiří - Otyepka, M. - Banáš, Pavel
Chemical Feasibility of the General Acid/Base Mechanism of glmS Ribozyme Self-Cleavage.
Biopolymers. Roč. 103, č. 10 (2015), s. 550-562. ISSN 0006-3525. E-ISSN 1097-0282
R&D Projects: GA MŠMT(CZ) ED1.1.00/02.0068; GA ČR(CZ) GAP208/12/1878
Institutional support: RVO:68081707
Keywords : MOLECULAR-DYNAMICS SIMULATIONS * ACTIVE-SITE GUANINE * HAIRPIN RIBOZYME
Subject RIV: BO - Biophysics
Impact factor: 2.248, year: 2015

In numerous Gram-positive bacteria, the glmS ribozyme or catalytic riboswitch regulates the expression of glucosamine-6-phosphate (GlcN6P) synthase via site-specific cleavage of its sugar-phosphate backbone in response to GlcN6P ligand binding. Biochemical data have suggested a crucial catalytic role for an active site guanine (G40 in Thermoanaerobacter tengcongensis, G33 in Bacillus anthracis). We used hybrid quantum chemical/molecular mechanical (QM/MM) calculations to probe the mechanism where G40 is deprotonated and acts as a general base. The calculations suggest that the deprotonated guanine G40(-) is sufficiently reactive to overcome the thermodynamic penalty arising from its rare protonation state, and thus is able to activate the A-1(2-OH) group toward nucleophilic attack on the adjacent backbone. Furthermore, deprotonation of A-1(2-OH) and nucleophilic attack are predicted to occur as separate steps, where activation of A-1(2-OH) precedes nucleophilic attack.
Permanent Link: http://hdl.handle.net/11104/0249403