Antibody Recognition of Cancer-Related Gangliosides and Their Mimics Investigated Using in silico Site Mapping

Abstract

Modified gangliosides may be overexpressed in certain types of cancer, thus, they are considered a valuable target in cancer immunotherapy. Structural knowledge of their interaction with antibodies is currently limited, due to the large size and high flexibility of these ligands. In this study, we apply our previously developed site mapping technique to investigate the recognition of cancer-related gangliosides by anti-ganglioside antibodies. The results reveal a potential ganglioside-binding motif in the four antibodies studied, suggesting the possibility of structural convergence in the anti-ganglioside immune response. The structural basis of the recognition of ganglioside-mimetic peptides is also investigated using site mapping and compared to ganglioside recognition. The peptides are shown to act as structural mimics of gangliosides by interacting with many of the same binding site residues as the cognate carbohydrate epitopes. These studies provide important clues as to the structural basis of immunological mimicry of carbohydrates.

Improvements, trends, and new ideas in molecular docking: 2012–2013 in review

“…An alternative, interaction‐based approach to the exploitation of pose ensemble was developed by Yuriev, Ramsland and co‐workers In this method, AutoMap – the site mapping technique – drives LigPlot to determine the hydrogen bonding and van der Waals interactions taking place between a target protein and each pose of a ligand ensemble. It then tallies these interactions per protein residue, normalizes the tallies, and maps them to the protein surface.…”

Latest developments in molecular docking: 2010–2011 in review

“…Another method, based on NMR-derived proximities of ligand protons to the target surface, was proposed, which improved docking accuracy from~50% to~70%. [132] A similar methodology was developed by Agostino et al [133][134][135] However, in their approach, a set of docked poses, rather than experimental structures, is used to derive the interactions required for pose filtering. The advantage of this method, compared with the one above, is that it is applicable to systems with no or only limited experimental structural data.…”

“…Also, because the method was developed for carbohydrates, particularly flexible ligands, the poses are also parsed by conformational filters, reflecting the conformational composition of the docked pose ensemble. The method was tested against a set of 20 antibody-carbohydrate systems [135,137] and 15 lectin-carbohydrate systems [134] and demonstrated a superior performance compared with considering the top-docked pose alone. It has also been successfully applied to peptide ligands.…”

Gangliosides and Antigangliosides in Malignant Melanoma

“…Several tumor gangliosides induced the synthesis of antiganglioside antibodies in melanoma patients [9,[85][86][87][88][89][90][91][92]. The role of these antibodies is a subject of great current interest in medical research [9,10,78,90,93].…”