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Unravelling the covalent binding of zampanolide and taccalonolide AJ to a minimalist representation of a human microtubule

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Abstract

Many natural products target mammalian tubulin but only a few can form a covalent bond and hence irreversibly affect microtubule function. Among them, zampanolide (ZMP) and taccalonolide AJ (TAJ) stand out, not only because they are very potent antitumor agents but also because the adducts they form with β-tubulin have been structurally characterized in atomic detail. By applying model building techniques, molecular orbital calculations, molecular dynamics simulations and hybrid QM/MM methods, we have gained insight into the 1,2- and 1,4-addition reactions of His229 and Asp226 to ZMP and TAJ, respectively, in the taxane-binding site of β-tubulin. The experimentally inaccessible precovalent complexes strongly suggest a water-mediated proton shuttle mechanism for ZMP adduct formation and a direct nucleophilic attack by the carboxylate of Asp226 on C22 of the C22R,C23R epoxide in TAJ. The M-loop, which is crucially important for interprotofilament interactions, is structured into a short helix in both types of complexes, mostly as a consequence of the fixation of the phenol ring of Tyr283 and the guanidinium of Arg284. As a side benefit, we obtained evidence supporting the existence of a commonly neglected intramolecular disulfide bond between Cys241 and Cys356 in β-tubulin that contributes to protein compactness and is absent in the βIII isotype associated with resistance to taxanes and other drugs.

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Abbreviations

DFTB:

Density functional-based tight-binding

MM-ISMSA:

Molecular mechanics-implicit solvent model surface area

QM/MM:

Quantum mechanics/molecular mechanics

sMD:

Steered molecular dynamics

uMD:

Unrestrained molecular dynamics

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Acknowledgements

We are grateful to Prof. Susan L. Mooberry (University of San Antonio, TX, USA) and Prof. Wei-shuo Fang (University of Beijing, China) for encouragement and helpful discussions.

Funding

Financial support from the Spanish Ministerio de Economía y Competitividad (SAF2015-64629-C2-2-R) and PharmaMar S.A.U. is gratefully acknowledged.

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  1. Pedro A. Sánchez-Murcia

    Present address: Institute of Theoretical Chemistry, University of Vienna, Währinger Str. 17, 1090, Vienna, Austria

Authors and Affiliations

  1. Area of Pharmacology, Department of Biomedical Sciences and “Unidad Asociada IQM-CSIC”, School of Medicine and Health Sciences, University of Alcalá, 28805, Alcalá de Henares, Madrid, Spain

    Pedro A. Sánchez-Murcia, Alberto Mills, Álvaro Cortés-Cabrera & Federico Gago

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  1. Pedro A. Sánchez-Murcia
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Contributions

Participated in research design: PAS-M and FG. Conducted experiments: PAS-M, AM, and FG. Contributed new analytic tools: AC-C. Performed data analysis: PAS-M, AM, AC-C, and FG. Wrote the manuscript: PAS-M and FG.

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Correspondence to Federico Gago.

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Sánchez-Murcia, P.A., Mills, A., Cortés-Cabrera, Á. et al. Unravelling the covalent binding of zampanolide and taccalonolide AJ to a minimalist representation of a human microtubule. J Comput Aided Mol Des 33, 627–644 (2019). https://doi.org/10.1007/s10822-019-00208-w

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