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

Hritz, Jozef; Läppchen, Tilman; Oostenbrink, Chris

doi:10.1007/s00249-010-0614-y

Cited by 18 publications

(15 citation statements)

References 44 publications

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“…), in this case with respect to GTP (Δ G GTP → X ), as shown in the third column of Table . The Δ G GTP → X are in line with previous results only using OSP . Moreover, the value of 5.6 ± 0.8 of Δ G H → Br is in excellent agreement with the TI‐LE/US results.…”

Section: Resultssupporting

confidence: 90%

Free‐energy differences between states with different conformational ensembles

Gárate

Oostenbrink

2013

J Comput Chem

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Multiple conformations separated by high-energy barriers represent a challenging problem in free-energy calculations due to the difficulties in achieving adequate sampling. We present an application of thermodynamic integration (TI) in conjunction with the local elevation umbrella sampling (LE/US) method to improve convergence in alchemical free-energy calculations. TI-LE/US was applied to the guanosine triphosphate (GTP) to 8-Br-GTP perturbation, molecules that present high-energy barriers between the anti and syn states and that have inverted preferences for those states. The convergence and reliability of TI-LE/US was assessed by comparing with previous results using the enhanced-sampling one-step perturbation (OSP) method. A linear interpolation of the end-state biasing potentials was sufficient to dramatically improve sampling along the chosen reaction coordinate. Conformational free-energy differences were also computed for the syn and anti states and compared to experimental and theoretical results. Additionally, a coupled OSP with LE/US was carried out, allowing the calculation of conformational and alchemical free energies of GTP and 8-substituted GTP analogs.

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Section: Resultssupporting

confidence: 90%

Free‐energy differences between states with different conformational ensembles

Gárate

Oostenbrink

2013

J Comput Chem

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“…This confirms but also improves upon previously reported results (26). The affinities of 8-Cl-GTP and 8-Br-GTP relative to GTP are compatible with recent free energy calculations, which take into account the effect of these substitutions in the dihedral angle distribution around the glycosidic bond (58). The results demonstrate that our method of measurement of modified nucleotides binding to the GTP site in FtsZ can serve to predict inhibitory effects on FtsZ polymerization.…”

Section: Discussionsupporting

confidence: 91%

Insights into Nucleotide Recognition by Cell Division Protein FtsZ from a mant-GTP Competition Assay and Molecular Dynamics

et al. 2010

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Essential cell division protein FtsZ forms the bacterial cytokinetic ring and is a target for new antibiotics. FtsZ monomers bind GTP and assemble into filaments. Hydrolysis to GDP at the association interface between monomers leads to filament disassembly. We have developed a homogeneous competition assay, employing the fluorescence anisotropy change of mant-GTP upon binding to nucleotide-free FtsZ, which detects compounds binding to the nucleotide site in FtsZ monomers and measures their affinities within the millimolar to 10 nM range. We have employed this method to determine the apparent contributions of the guanine, ribose, and the α-, β-, and γ-phosphates to the free energy change of nucleotide binding. Similar relative contributions have also been estimated through molecular dynamics and binding free energy calculations, employing the crystal structures of FtsZ-nucleotide complexes. We find an energetically dominant contribution of the β-phosphate, comparable to the whole guanosine moiety. GTP and GDP bind with similar observed affinity to FtsZ monomers. Loss of the regulatory γ-phosphate results in a predicted accommodation of GDP which has not been observed in the crystal structures. The binding affinities of a series of C8-substituted GTP analogues, known to inhibit FtsZ but not eukaryotic tubulin assembly, correlate with their inhibitory capacity on FtsZ polymerization. Our methods permit testing of FtsZ inhibitors targeting its nucleotide site, as well as compounds from virtual screening of large synthetic libraries. Our results give insight into the FtsZ-nucleotide interactions, which could be useful in the rational design of new inhibitors, especially GTP phosphate mimetics.

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“…For accurate modelling of flexible ligand systems the energetic offset (ligand strain) between unbound conformation and receptor-bound conformation needs to be included. Sufficient conformational sampling of the ligand in unbound state can help to unravel the pre-existing population of the bound state, and thus its free energy difference, if a mechanism of conformational selection applies to the studied system [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Kinetic barriers in the isomerization of substituted ureas: implications for computer-aided drug design

Loeffler

Ehmki

Fuchs

et al. 2016

J Comput Aided Mol Des

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Urea derivatives are ubiquitously found in many chemical disciplines. N,N′-substituted ureas may show different conformational preferences depending on their substitution pattern. The high energetic barrier for isomerization of the cis and trans state poses additional challenges on computational simulation techniques aiming at a reproduction of the biological properties of urea derivatives. Herein, we investigate energetics of urea conformations and their interconversion using a broad spectrum of methodologies ranging from data mining, via quantum chemistry to molecular dynamics simulation and free energy calculations. We find that the inversion of urea conformations is inherently slow and beyond the time scale of typical simulation protocols. Therefore, extra care needs to be taken by computational chemists to work with appropriate model systems. We find that both knowledge-driven approaches as well as physics-based methods may guide molecular modelers towards accurate starting structures for expensive calculations to ensure that conformations of urea derivatives are modeled as adequately as possible.Electronic supplementary materialThe online version of this article (doi:10.1007/s10822-016-9913-4) contains supplementary material, which is available to authorized users.

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

Cited by 18 publications

References 44 publications

Free‐energy differences between states with different conformational ensembles

Free‐energy differences between states with different conformational ensembles

Insights into Nucleotide Recognition by Cell Division Protein FtsZ from a mant-GTP Competition Assay and Molecular Dynamics

Kinetic barriers in the isomerization of substituted ureas: implications for computer-aided drug design

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