Computational modeling and molecular dynamics simulations of a cyclic peptide mimotope of the CD52 antigen complexed with CAMPATH-1H antibody

Athanassios Stavrakoudis (1)

1 Economics

A peptide mimotope of the CD52 antigen with the sequence T1SSPSAD7 has been co-crystallized with the CAMPATH-1H antibody. Molecular dynamics simulations in explicit water of the T1SSPSAD7 peptide in both antibody free and bound states showed that the peptide's β-turn was remained stable in the bound state but it was eliminated in the free state. Based on the observation that Thr1 and Ala6 residues made close contacts through their side chain, a new peptide mimotope is proposed: (S,S)-C1SSPSCD7. Thr1 and Ala6 residues have been mutated in Cys residues and a disulfide bond has been imposed. The new analogue has been simulated in both antibody bound and free states with molecular dynamics in explicit water. It was found that the peptide remained in stable β-turn conformation, both in complexed and free states. The difference in configurational entropy was estimated to be 0.15 kJK-1mol-1. However, despite the structural similarity, the cyclic analogue lost more than 25% of its buried surface area contact with the antibody and a couple of critical hydrogen bond interactions were broken. It is concluded that design of cyclic analogues that mimic the bound conformation of peptides should be carefully performed and conformational “freezing” does not necessarily guarantee better binding.

Mots clés: Physical Sciences

Athanassios Stavrakoudis. Computational modeling and molecular dynamics simulations of a cyclic peptide mimotope of the CD52 antigen complexed with CAMPATH-1H antibody. Molecular Simulation, 2010, 36 (02), pp.127-137. ⟨10.1080/08927020903124593⟩. ⟨hal-00564475⟩