Docking of combinatorial peptide libraries into a broadly cross‐reactive human IgM

Abstract

A monoclonal IgM cryoglobulin with diverse binding behavior was isolated from a patient (Mez) with Waldenström's macroglobulinemia. It gave very high titers in the binding of combinatorially synthesized libraries of peptides ranging in size from two to eight residues. The crystal structure of Mez Fv revealed that the binding site was divided into two cavities of unequal volumes with dimensions and chemical properties that were compatible with the binding of peptides. Access to this unique combination of structural information and peptide binding data led us to carry out Mez-peptide docking simulations to gain insight into the Mez binding propensities. In the present article, the results for docking of five peptide libraries are combined with discussions of the methods and approximations involved in the docking process. We analyze the origins of peptide binding affinity for Mez IgM in terms of its cross-reactivity and its structural preferences.

Structural, antigenic and evolutionary analyses of immunoglobulins and T cell receptors

“…Our findings with natural IgM monoclonals of humans and mice thus paralleled observations by the Berlin group who studied in detail the capacity of an induced murine IgG monoclonal antibody to HIV gp41 for its capacity to bind unrelated peptides Kramer et al, 1997). Allen Edmundson's group Ramsland et al, 2000Ramsland et al, , 2001Yuriev et al, 2001) and ours share a common interest in defining the structural parameters of antibody combining sites that condition restrictive specificity or, alternatively, epitope recognition promiscuity and even polyreactivity. Our studies to date indicate that these are properties of the combining sites of IgM molecules representing the two most divergent species to express antibodies and the combinatorial immune system, sharks and humans.…”

Mcg light chain dimer as a model system for ligand design: a docking study

“…Previously, while docking peptides of different lengths into the large binding site of an IgM antibody (Mez; Yuriev et al, , 2002, we observed a trend opposite to the one described here. Namely, by comparing the docking ranks to the relative binding strengths determined by ELISA, we detected a lack of correlation between the experiment and simulation for the shorter dipeptides (termed 'small balls in a large hole'; Yuriev et al, 2001) and a much better correlation for the longer octapeptides.…”

“…Owing to the rigid nature of the docking applied here (i.e. receptor shape is not adaptable during docking; Yuriev et al, 2001), it was impossible to predict the wedging of the ligand in between the residues of the binding site. However, it was encouraging to note the location of the anchoring N-acetyl group in the docked structure 14 [ Fig.…”

Molecular Simulations of Carbohydrates with a Fucose-Binding Burkholderia ambifaria Lectin Suggest Modulation by Surface Residues Outside the Fucose-Binding Pocket

“…Only poses that passed the glycosidic torsion filter requirements (see above), were used for site mapping, following a previously developed method (Yuriev et al, 2001; Agostino et al, 2009b, 2011, 2013; Dingjan et al, 2015a). In brief, each individual hydrogen bond made by a particular BambL residue was counted toward the hydrogen-bond tally.…”