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

Laurence Leherte, Axel Petit, Denis Jacquemin, Daniel Vercauteren, Adèle Laurent

Research output: Contribution to conferencePoster

5 Downloads (Pure)

Abstract

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).

References
1) Gokhale A, Weldeghiorghis ThK, Taneja V, Satyanarayanajois D (2011) Conformationally constrained peptides from CD2 to modulate protein-protein interactions between CD2 and CD58. J Med Chem 54:5307-5319
2) Gokhale A, Kanthala S, Latendresse J, Taneja V, Satyanarayana SD (2013) Immunosuppression by co-stimulatory molecules: Inhibition of CD2-CD48/CD58 interaction by peptides from CD2 to suppress progression of collagen-induced arthritis in mice. Chem Biol Drug Des 82:106-118
3) Sable R, Durek T, Taneja V, Craik DJ, Pallerla S, Gauthier T, Jois S (2016) Constrained cyclic peptides as immunomodulatory inhibitors of the CD2:CD58 protein-protein interaction. ACS Chem Biol 11:2366-2374
4) Gokhale AS, Sable R, Walker JD, McLaughlin L, Kousoulas KG, Satyanarayana SD (2015) Inhibition of cell adhesion and immune responses in the mouse model of collagen-induced arthritis with a peptidomimetic that blocks CD2-CD58
interface interactions. Biopolymers 104:733-742
Original languageEnglish
Publication statusPublished - 23 Nov 2018
EventAnnual One-Day Meeting on Medicinal Chemistry - MedChem2018 - UNamur, Namur, Belgium
Duration: 23 Nov 201823 Nov 2018

Meeting

MeetingAnnual One-Day Meeting on Medicinal Chemistry - MedChem2018
CountryBelgium
CityNamur
Period23/11/1823/11/18

Fingerprint

Molecular dynamics
Ligands
Proteins
Hydrogen bonds
Collagen
Peptidomimetics
Cyclic Peptides
Peptides
Biopolymers
T-cells
Cell adhesion
Crystal structure
Education
Molecules
Water
Pharmaceutical Preparations

Cite this

Leherte, L., Petit, A., Jacquemin, D., Vercauteren, D., & Laurent, A. (2018). Investigation of cyclic ligands inhibiting CD2-CD58 interactions using molecular dynamics and molecular docking approaches. Poster session presented at Annual One-Day Meeting on Medicinal Chemistry - MedChem2018, Namur, Belgium.
Leherte, Laurence ; Petit, Axel ; Jacquemin, Denis ; Vercauteren, Daniel ; Laurent, Adèle. / Investigation of cyclic ligands inhibiting CD2-CD58 interactions using molecular dynamics and molecular docking approaches. Poster session presented at Annual One-Day Meeting on Medicinal Chemistry - MedChem2018, Namur, Belgium.
@conference{5156a08036af432c99a2cc3d64eb872b,
title = "Investigation of cyclic ligands inhibiting CD2-CD58 interactions using molecular dynamics and molecular docking approaches",
abstract = "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 ofHigher Education and Research, in the framework of the Hubert Curien partnerships (PHC Tournesol “DoIFAD” #40638PL).References1) Gokhale A, Weldeghiorghis ThK, Taneja V, Satyanarayanajois D (2011) Conformationally constrained peptides from CD2 to modulate protein-protein interactions between CD2 and CD58. J Med Chem 54:5307-53192) Gokhale A, Kanthala S, Latendresse J, Taneja V, Satyanarayana SD (2013) Immunosuppression by co-stimulatory molecules: Inhibition of CD2-CD48/CD58 interaction by peptides from CD2 to suppress progression of collagen-induced arthritis in mice. Chem Biol Drug Des 82:106-1183) Sable R, Durek T, Taneja V, Craik DJ, Pallerla S, Gauthier T, Jois S (2016) Constrained cyclic peptides as immunomodulatory inhibitors of the CD2:CD58 protein-protein interaction. ACS Chem Biol 11:2366-23744) Gokhale AS, Sable R, Walker JD, McLaughlin L, Kousoulas KG, Satyanarayana SD (2015) Inhibition of cell adhesion and immune responses in the mouse model of collagen-induced arthritis with a peptidomimetic that blocks CD2-CD58interface interactions. Biopolymers 104:733-742",
author = "Laurence Leherte and Axel Petit and Denis Jacquemin and Daniel Vercauteren and Ad{\`e}le Laurent",
year = "2018",
month = "11",
day = "23",
language = "English",
note = "Annual One-Day Meeting on Medicinal Chemistry - MedChem2018 ; Conference date: 23-11-2018 Through 23-11-2018",

}

Leherte, L, Petit, A, Jacquemin, D, Vercauteren, D & Laurent, A 2018, 'Investigation of cyclic ligands inhibiting CD2-CD58 interactions using molecular dynamics and molecular docking approaches' Annual One-Day Meeting on Medicinal Chemistry - MedChem2018, Namur, Belgium, 23/11/18 - 23/11/18, .

Investigation of cyclic ligands inhibiting CD2-CD58 interactions using molecular dynamics and molecular docking approaches. / Leherte, Laurence; Petit, Axel; Jacquemin, Denis; Vercauteren, Daniel; Laurent, Adèle.

2018. Poster session presented at Annual One-Day Meeting on Medicinal Chemistry - MedChem2018, Namur, Belgium.

Research output: Contribution to conferencePoster

TY - CONF

T1 - Investigation of cyclic ligands inhibiting CD2-CD58 interactions using molecular dynamics and molecular docking approaches

AU - Leherte, Laurence

AU - Petit, Axel

AU - Jacquemin, Denis

AU - Vercauteren, Daniel

AU - Laurent, Adèle

PY - 2018/11/23

Y1 - 2018/11/23

N2 - 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 ofHigher Education and Research, in the framework of the Hubert Curien partnerships (PHC Tournesol “DoIFAD” #40638PL).References1) Gokhale A, Weldeghiorghis ThK, Taneja V, Satyanarayanajois D (2011) Conformationally constrained peptides from CD2 to modulate protein-protein interactions between CD2 and CD58. J Med Chem 54:5307-53192) Gokhale A, Kanthala S, Latendresse J, Taneja V, Satyanarayana SD (2013) Immunosuppression by co-stimulatory molecules: Inhibition of CD2-CD48/CD58 interaction by peptides from CD2 to suppress progression of collagen-induced arthritis in mice. Chem Biol Drug Des 82:106-1183) Sable R, Durek T, Taneja V, Craik DJ, Pallerla S, Gauthier T, Jois S (2016) Constrained cyclic peptides as immunomodulatory inhibitors of the CD2:CD58 protein-protein interaction. ACS Chem Biol 11:2366-23744) Gokhale AS, Sable R, Walker JD, McLaughlin L, Kousoulas KG, Satyanarayana SD (2015) Inhibition of cell adhesion and immune responses in the mouse model of collagen-induced arthritis with a peptidomimetic that blocks CD2-CD58interface interactions. Biopolymers 104:733-742

AB - 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 ofHigher Education and Research, in the framework of the Hubert Curien partnerships (PHC Tournesol “DoIFAD” #40638PL).References1) Gokhale A, Weldeghiorghis ThK, Taneja V, Satyanarayanajois D (2011) Conformationally constrained peptides from CD2 to modulate protein-protein interactions between CD2 and CD58. J Med Chem 54:5307-53192) Gokhale A, Kanthala S, Latendresse J, Taneja V, Satyanarayana SD (2013) Immunosuppression by co-stimulatory molecules: Inhibition of CD2-CD48/CD58 interaction by peptides from CD2 to suppress progression of collagen-induced arthritis in mice. Chem Biol Drug Des 82:106-1183) Sable R, Durek T, Taneja V, Craik DJ, Pallerla S, Gauthier T, Jois S (2016) Constrained cyclic peptides as immunomodulatory inhibitors of the CD2:CD58 protein-protein interaction. ACS Chem Biol 11:2366-23744) Gokhale AS, Sable R, Walker JD, McLaughlin L, Kousoulas KG, Satyanarayana SD (2015) Inhibition of cell adhesion and immune responses in the mouse model of collagen-induced arthritis with a peptidomimetic that blocks CD2-CD58interface interactions. Biopolymers 104:733-742

M3 - Poster

ER -

Leherte L, Petit A, Jacquemin D, Vercauteren D, Laurent A. Investigation of cyclic ligands inhibiting CD2-CD58 interactions using molecular dynamics and molecular docking approaches. 2018. Poster session presented at Annual One-Day Meeting on Medicinal Chemistry - MedChem2018, Namur, Belgium.