Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZReportar como inadecuado




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European Biophysics Journal

, Volume 39, Issue 12, pp 1573–1580

First Online: 18 June 2010Received: 01 April 2010Revised: 21 May 2010Accepted: 26 May 2010

Abstract

The FtsZ protein is a self-polymerizing GTPase that plays a central role in bacterial cell division. Several C8-substituted GTP analogs are known to inhibit the polymerization of FtsZ by competing for the same binding site as its endogenous activating ligand GTP. Free energy calculations of the relative binding affinities to FtsZ for a set of five C8-substituted GTP analogs were performed. The calculated values agree well with the available experimental data, and the main contribution to the free energy differences is determined to be the conformational restriction of the ligands. The dihedral angle distributions around the glycosidic bond of these compounds in water are known to vary considerably depending on the physicochemical properties of the substituent at C8. However, within the FtsZ protein, this substitution has a negligible influence on the dihedral angle distributions, which fall within the narrow range of −140° to −90° for all investigated compounds. The corresponding ensemble average of the coupling constants JC4,H1′ is calculated to be 2.95 ± 0.1 Hz. The contribution of the conformational selection of the GTP analogs upon binding was quantified from the corresponding populations. The obtained restraining free energy values follow the same trend as the relative binding affinities to FtsZ, indicating their dominant contribution.

KeywordsGTP analogs FtsZ One-step free energy perturbation Conformational selection Restraining free energy Ensemble average Heteronuclear coupling constant  Download fulltext PDF



Autor: Jozef Hritz - Tilman Läppchen - Chris Oostenbrink

Fuente: https://link.springer.com/



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