Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ |
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Authors: | Jozef Hritz Tilman Läppchen Chris Oostenbrink |
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Institution: | (1) Leiden-Amsterdam Center for Drug Research, Section of Molecular Toxicology, Department of Chemistry and Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands;(2) Department of Biomolecular Engineering, Philips Research, High Tech Campus 11, M/S WBC02 P263, 5656 AE Eindhoven, The Netherlands;(3) Institute of Molecular Modeling and Simulation, University of Natural Resources and Applied Life Sciences, Muthgasse 18, 1190 Vienna, Austria |
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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 3
J(C4,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. |
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Keywords: | |
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