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Investigating cyclic peptides inhibiting CD2–CD58 interactions through molecular dynamics and molecular docking methods

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Abstract

The CD2–CD58 protein–protein interaction is known to favor the recognition of antigen presenting cells by T cells. The structural, energetics, and dynamical properties of three known cyclic CD58 ligands, named P6, P7, and RTD-c, are studied through molecular dynamics (MD) simulations and molecular docking calculations. The ligands are built so as to mimic the C and F β-strands of protein CD2, connected via turn inducers. The MD analyses focus on the location of the ligands with respect to the experimental binding site and on the direct and water-mediated hydrogen bonds (H bonds) they form with CD58. Ligand P6, with a sequence close to the experimental β-strands of CD2, presents characteristics that explain its higher experimental affinity, e.g., the lower mobility and flexibility at the CD58 surface, and the larger number and occurrence frequency of ligand-CD58 H bonds. For the two other ligands, the structural modifications lead to changes in the binding pattern with CD58 and its dynamics. In parallel, a large set of molecular docking calculations, carried out with various search spaces and docking algorithms, are compared to provide a consensus view of the preferred ligand binding modes. The analysis of the ligand side chain locations yields results that are consistent with the CD2–CD58 crystal structure and suggests various binding modes of the experimentally identified hot spot of the ligands, i.e., Tyr86. P6 is shown to form a number of contacts that are also present in the experimental CD2–CD58 structure.

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Acknowledgements

The authors thank the reviewers for their comments that helped to improve the manuscript, as well as Dr. Jose Ceron-Carrasco and Horacio Pérez Sánchez for numerous discussions. Frédéric Wautelet and Laurent Demelenne are gratefully acknowledged for program installation and maintenance. The research used resources of the ‘Plateforme Technologique de Calcul Intensif (PTCI)’ (http://www.ptci.unamur.be) located at the University of Namur, Belgium, which is supported by the F.R.S.-FNRS convention 2.5020.11. The PTCI is member of the ‘Consortium des Équipements de Calcul Intensif (CÉCI)’ (http://www.ceci-hpc.be). This research used as well French resources of (1) the GENCI-CINES/IDRIS (Grants A0020805117) and (2) CCIPL (Centre de Calcul Intensif des Pays de Loire). ADL thanks the ‘Région Pays de la Loire (Dynamique scientifique Piramid)’ for the support. The authors also thank the Interuniversity Attraction Pole program no. 7/05: ‘Functional supramolecular systems’ initiated by the Belgian Science Policy Office. Funding was provided by the Wallonie-Bruxelles International WBI (PHC Tournesol DoIFAD) and the Belgian National Foundation for Scientific Research (FNRS), by the French Ministry of Foreign and European Affairs, and by the Ministry of Higher Education and Research, in the framework of the Hubert Curien partnerships (PHC Tournesol #40638PL).

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Authors and Affiliations

  1. Laboratoire de Physico-Chimie Informatique, Unité de Chimie Physique Théorique et Structurale, Department of Chemistry, NAmur MEdicine and Drug Innovation Center (NAMEDIC), Namur Institute of Structured Matter (NISM), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium

    Laurence Leherte, Axel Petit & Daniel P. Vercauteren

  2. University of Nantes, CEISAM UMR CNRS 6230, UFR Sciences et Techniques, 2 Rue de la Houssinière, BP 92208, 44322, Nantes Cedex 03, France

    Denis Jacquemin & Adèle D. Laurent

  3. Institut Universitaire de France, 103 Bd St Michel, 75005, Paris Cedex 5, France

    Denis Jacquemin

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  1. Laurence Leherte
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Correspondence to Laurence Leherte.

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Leherte, L., Petit, A., Jacquemin, D. et al. Investigating cyclic peptides inhibiting CD2–CD58 interactions through molecular dynamics and molecular docking methods. J Comput Aided Mol Des 32, 1295–1313 (2018). https://doi.org/10.1007/s10822-018-0172-4

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  • DOI: https://doi.org/10.1007/s10822-018-0172-4

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