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Conformational analysis of a polyconjugated protein-binding ligand by joint quantum chemistry and polarizable molecular mechanics. Addressing the issues of anisotropy, conjugation, polarization, and multipole transferability

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Abstract

We investigate the conformational properties of a potent inhibitor of neuropilin-1, a protein involved in cancer processes and macular degeneration. This inhibitor consists of four aromatic/conjugated fragments: a benzimidazole, a methylbenzene, a carboxythiourea, and a benzene-linker dioxane, and these fragments are all linked together by conjugated bonds. The calculations use the SIBFA polarizable molecular mechanics procedure. Prior to docking simulations, it is essential to ensure that variations in the ligand conformational energy upon rotations around its six main-chain torsional bonds are correctly represented (as compared to high-level ab initio quantum chemistry, QC). This is done in two successive calibration stages and one validation stage. In the latter, the minima identified following independent stepwise variations of each of the six main-chain torsion angles are used as starting points for energy minimization of all the torsion angles simultaneously. Single-point QC calculations of the minimized structures are then done to compare their relative energies ΔE conf to the SIBFA ones. We compare three different methods of deriving the multipoles and polarizabilities of the central, most critical moiety of the inhibitor: carboxythiourea (CTU). The representation that gives the best agreement with QC is the one that includes the effects of the mutual polarization energy E pol between the amide and thioamide moieties. This again highlights the critical role of this contribution. The implications and perspectives of these findings are discussed.

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Acknowledgments

We wish to thank the Grand Equipement National de Calcul Intensif (GENCI): Institut du Developpement et des Ressources en Informatique Scientifique (IDRIS), Centre Informatique de l’Enseignement Superieur (CINES), France, project no. x2009-075009), and the Centre de Ressources Informatiques de Haute Normandie (CRIHAN, Rouen, France), project 1998053.

We wish to acknowledge a CIFRE grant allotted to Elodie Goldwaser in the course of her Ph.D. thesis.

We are pleased to thank Drs. Lucia Borriello and Pascal Dao for enriching discussions during the course of this work.

Author information

Author notes

  1. Luc Demange

    Present address: Institut de Chimie de Nice (ICN), UMR 7272 CNRS, Université de Nice Sophia-Antipolis, Parc Valrose, 06000, Nice, France

Authors and Affiliations

  1. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601, UFR Biomédicale, Université ParisDescartes, 45, rue des Saints-Pères, 75006, Paris, France

    Elodie Goldwaser, Luc Demange, Christiane Garbay, Françoise Raynaud & Nohad Gresh

  2. Laboratoire de Chimie Théorique, Sorbonne Universités, UPMC, Paris 6, case courrier 137, 4, place Jussieu, F75252, Paris, France

    Elodie Goldwaser, Benoit de Courcy & Jean-Philip Piquemal

  3. Tragex Pharma, 29, rue Marcel Dassault, 92100, Boulogne Billancourt, France

    Reda Hadj-Slimane

Authors
  1. Elodie Goldwaser
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  2. Benoit de Courcy
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  3. Luc Demange
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  4. Christiane Garbay
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  6. Reda Hadj-Slimane
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  7. Jean-Philip Piquemal
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  8. Nohad Gresh
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Corresponding authors

Correspondence to Jean-Philip Piquemal or Nohad Gresh.

Electronic supplementary material

Below is the link to the electronic supplementary material.

S1

Intermolecular interaction energies (kcal/mol) of water with sites in CTU, with a range of interaction distances that are shorter than the equilibrium distance considered. The energy contributions are listed as pairs of rows: the first row corresponds to the RVS values and the second to the SIBFA ones. The distances given in the first row of results are in Å. (DOC 355 kb)

S2

Torsion angles (in degrees) of lig-47 in its energy-minimized conformations. (DOC 49 kb)

S3

Construction of CTU by assembling thioamide and amide fragments. Intermolecular interaction energies (kcal/mol) of water with sites in CTU are shown, with a range of distances that are shorter than equilibrium distance considered. The energy contributions are listed as pairs of rows: the first row corresponds to the RVS values and the second to the SIBFA ones. The distances given in the first row of results are in Å. (DOC 243 kb)

S4

Construction of CTU by assemblingsp 2 amine, thioaldehyde, and aldehyde fragments. Intermolecular interaction energies (kcal/mol) and the various contributions to those energies in the binding of a probe water molecule with sites in CTU. The energy contributions are listed as pairs of rows: the first row corresponds to the RVS values and the second to the SIBFA ones. Distances given in the first row of results are in Å. (DOC 60 kb)

S5

Construction of CTU by assemblingsp 2 amine, thioaldehyde, and aldehyde fragments. Variations in the conformational energy of lig-47 as functions of the torsion anglesφ1 andφ3–φ7 are shown. (DOC 383 kb)

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Goldwaser, E., de Courcy, B., Demange, L. et al. Conformational analysis of a polyconjugated protein-binding ligand by joint quantum chemistry and polarizable molecular mechanics. Addressing the issues of anisotropy, conjugation, polarization, and multipole transferability. J Mol Model 20, 2472 (2014). https://doi.org/10.1007/s00894-014-2472-5

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  • DOI: https://doi.org/10.1007/s00894-014-2472-5

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