Paratope Plasticity in Diverse Modes Facilitates Molecular Mimicry in Antibody Response

Abstract

The immune response against methyl-α-d-mannopyranoside mimicking 12-mer peptide (DVFYPYPYASGS) was analyzed at the molecular level towards understanding the equivalence of these otherwise disparate Ags. The Ab 7C4 recognized the immunizing peptide and its mimicking carbohydrate Ag with comparable affinities. Thermodynamic analyses of the binding interactions of both molecules suggested that the mAb 7C4 paratope lacks substantial conformational flexibility, an obvious possibility for facilitating binding to chemically dissimilar Ags. Favorable changes in entropy during binding indicated the importance of hydrophobic interactions in recognition of the mimicking carbohydrate Ag. Indeed, the topology of the Ag-combining site was dominated by a cluster of aromatic residues, contributed primarily by the specificity defining CDR H3. Epitope-mapping analysis demonstrated the critical role of three aromatic residues of the 12-mer in binding to the Ab. Our studies delineate a mechanism by which mimicry is manifested in the absence of either structural similarity of the epitopes or conformational flexibility in the paratope. An alternate mode of recognition of dissimilar yet mimicking Ags by the anti-peptide Ab involves plasticity associated with aromatic/hydrophobic and van der Waals interactions. Thus, antigenic mimicry may be a consequence of paratope-specific modulations rather than being dependent only on the properties of the epitope. Such modulations may have evolved toward minimizing the consequences of antigenic variation by invading pathogens.

The immunoglobulin constant region contributes to affinity and specificity

“…Structural evidence has suggested that Abs with high affinity manifest a ''lock and key'' type of binding, involving a higher amount of polar and charged interactions [16][17][18]22] that contribute to the rigidity of the Ag-binding site and to a higher binding energy for the AbAg interaction [16,18,22,23]. By contrast, more crossreactive Abs show fewer electrostatic contributions to Ab-Ag binding and an increase in hydrophobicity [24], thus allowing for greater molecular flexibility [25]. Flexible areas have more intermolecular interactions, via polar and charged residues, in comparison to the rigid regions [17,18].…”

Computational de novo design of antibodies binding to a peptide with high affinity

“…Using OptMAVEn, we, de novo, designed single‐chain antibodies (scFvs) against the dodecapeptide antigen DVFYPYPYASGS. The dodecapeptide with its Tyr‐Pro‐Tyr motif mimics the carbohydrate methyl α‐ D ‐mannopyranoside, which has been studied extensively since it is the recognition target of lectin concanavalin A (con A) and mAb‐2D10 (Krishnan et al, ; Tapryal et al, ). Association with the two antigens (dodecapeptide and methyl α‐ D ‐mannopyranoside) occurs at different sites for con A.…”

Characterization of structurally defined epitopes recognized by monoclonal antibodies produced by chronic lymphocytic leukemia B cells

“…Because little is known about the chemical nature of important antigens, that is, whether they are proteins, carbohydrates, or lipids, peptide phage display technology was used to identify ligands for CLL mAbs. This approach has successfully identified mimetic epitopes of proteins, 23 carbohydrates, [24][25][26] lipids, 27 and DNA. 28 Our data indicate that phage display is a feasible technique to identify and characterize ligands binding to M-CLL and U-CLL.…”