Identifying the epitope of an antibody is a key step in understanding its function and its potential as a therapeutic. Sequence-based clonal clustering can identify antibodies with similar epitope complementarity, however, antibodies from markedly different lineages but with similar structures can engage the same epitope. We describe a novel computational method for epitope profiling based on structural modelling and clustering. Using the method, we demonstrate that sequence dissimilar but functionally similar antibodies can be found across the Coronavirus Antibody Database, with high accuracy (92% of antibodies in multiple-occupancy structural clusters bind to consistent domains). Our approach functionally links antibodies with distinct genetic lineages, species origins, and coronavirus specificities. This indicates greater convergence exists in the immune responses to coronaviruses than is suggested by sequence-based approaches. Our results show that applying structural analytics to large class-specific antibody databases will enable high confidence structure-function relationships to be drawn, yielding new opportunities to identify functional convergence hitherto missed by sequence-only analysis. Author summary Antibodies are a key component of the immune system that combat pathogens by binding to a defined region of their molecular surface (known as an ‘epitope’). The ability to map which antibodies target the same epitopes is crucial when designing non-competing antibody therapeutics or predicting the influence of pathogen mutation on population immunity. While one can use laboratory experiments to deduce when pairs of antibodies engage the same epitope, such experiments are very expensive and time consuming if used to compare on the order of thousands of antibodies. In this work, we report a new computational algorithm (SPACE) that clusters antibodies that target the same epitope based on their predicted 3D structure, as binding site structure is a property often conserved between binders complementary to the same epitope. Unlike existing antibody epitope profiling tools which assume two antibodies must share a high sequence identity/similar genetic basis to engage the same region, our orthogonal method can detect broader patterns of convergent evolution across binders to different pathogen strains, and between antibodies with different genetic and even species origins.
【초록키워드】 Structure, Evolution, antibodies, coronavirus, immune response, Mutation, antibody, Genetic, immune system, database, binding site, Laboratory, Antibody therapeutics, Epitopes, pathogen, immune responses, Algorithm, therapeutic, Lineage, Clustering, Cluster, Pathogens, experiment, molecular, population immunity, convergent evolution, epitope, lineages, 3D structure, Strains, binding, Analysis, complementary, Space, domains, approaches, sequence, property, computational method, high accuracy, Specificities, while, identifying, structure-function, approach, greater, defined, predicted, identify, detect, conserved, functional, indicate, suggested, engage, yielding, 【제목키워드】 demonstrated,