Ab-Ligity: Identifying sequence-dissimilar antibodies that bind to the same epitope

Abstract

Motivation: Solving the structure of an antibody-antigen complex gives atomic level information of the interactions between an antibody and its antigen, but such structures are expensive and hard to obtain. Alternative experimental sources include epitope mapping and binning experiments which can be used as a surrogate to identify key interacting residues. However, their resolution is usually not sufficient to identify if two antibodies have identical interactions. Computational approaches to this problem have so far been based on the premise that antibodies with similar sequences behave similarly. Such approaches will fail to identify sequence-distant antibodies that target the same epitope. Results: We present Ab-Ligity, a structure-based similarity measure tailored to antibodyantigen interfaces. Using predicted paratopes on model antibody structures, we assessed our ability to identify those antibodies that target highly similar epitopes. Most antibodies adopting similar binding modes can be identified from sequence similarity alone, using methods such as clonotyping. In the challenging subset where the antibody sequences differ significantly, Ab-Ligity is still able to predict antibodies that would bind to highly similar epitopes (area under the precision-recall curve of 0.86). We compared Ab-Ligity's performance to an existing tool InterComp, and showed improved performance alongside a significant speed-up. These results suggest that Ab-Ligity will allow the identification of diverse (sequence-dissimilar) antibodies that bind to the same epitopes from large datasets such as immune repertoires. Availability: http://opig.stats.ox.ac.uk/resources Contact: deane@stats.ox.ac.uk Supplementary information: Supplementary Materials are available at Biorxiv.

The allosteric modulation of complement C5 by knob domain peptides

“…The paratopes of K8 and K92 contain 18 and 10 residues, respectively, which are within the typical range of antibody paratope sizes ( Figure 3—figure supplement 4A ). Given this similarity in size, we searched for structurally and physicochemically similar antibody paratopes from the 924 antibody complexes but no similar paratope sites were found ( Wong et al, 2020 ). While the limited examples preclude firm conclusions, this lack of similarity could be due to either the unusual fold of the knob domains or the differences in paratope amino acid composition.…”

A computational method for immune repertoire mining that identifies novel binders from different clonotypes, demonstrated by identifying anti-pertussis toxoid antibodies

“…Antibodies from different clonotypes have been observed to converge on the same binding site. [28][29][30][31] We hypothesize that these functionally convergent antibodies may use the same paratope for interaction, and examined SAbDab 32 for evidence that antibodies with similar paratopes bind to the same epitope. We defined the epitope and paratope as those residues with any atom within 4.5 Å of any residue in the cognate antibody or antigen, respectively, and consider only the heavy chains of the antibodies because in most BCR sequencing experiments only heavy chain sequences are available.…”

“… 5 , 10 The majority of antibodies binding to the same epitope in antibody-antigen complex structures in the Structural Antibody Database (SAbDab, a database of experimentally solved antibody and antibody-antigen complex structures) have highly similar CDRH3s. 28 However, it has also been observed that multiple clonotypes may converge on the same epitope. For example, Scheid and colleagues identified clonotypes from distinct immunoglobulin heavy chain variable (IGHV) gene subgroups converging on the CD4 binding site in gp120.…”

“… 31 Wong and colleagues identified 190 pairs of antibodies with sub-80% CDRH3 amino acid identity binding to the same epitope within SAbDab. 28 , 32 This convergence between clonotypes offers the potential to improve our understanding of the functional landscape of BCR repertoires; large-scale functional convergence between lineages could, for example, explain the apparent scarcity of public clonotypes. 33 This hypothesis is supported by evidence that, while clonotypes are infrequently shared between individuals, the range of antibody structures that these clonotypes generate is more similar between individuals.…”

The allosteric modulation of Complement C5 by knob domain peptides

“…The paratopes of K8 and K92 contain 18 and 10 residues, respectively, which are within the typical range of antibody paratope sizes (Supplementary 2.14). Given this similarity in size, we searched for structurally and physicochemically similar antibody paratopes from the 924 antibody complexes but no similar paratope sites were found (Wong et al, 2020). While the limited examples preclude firm conclusions, this lack of similarity could be due either to the unusual fold of the knob domains or to differences in paratope amino acid composition.…”