Investigation of cyclic ligands inhibiting CD2-CD58 interactions using molecular dynamics and molecular docking approaches

The CD2-CD58 protein-protein interaction is known to favor the recognition of antigen presenting cells by T cells. Molecular Dynamics (MD) and molecular docking calculations are carried out to study the structural, energetics, and dynamical properties of three known cyclic CD58 ligands, named P6 [1-3], P7 [1,4], and RTD-c [3]. Each ligand, connected via turn inducers, mimics the C and F β-strands of protein CD2. The MD analyses focus on the location of the ligands on the surface of CD58 and on the direct and water-mediated hydrogen bonds (Hbonds) they form with that receptor. 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 Hbonds. 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 suggest 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.
This work is supported by the Wallonie-Bruxelles International (WBI) 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 “DoIFAD” #40638PL).

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