Specific attributes of the V<sub>L</sub>domain influence both the structure and structural variability of CDR-H3 through steric effects

Guloglu, Bora; Deane, Charlotte M.

doi:10.1101/2023.05.16.540974

Cited by 3 publications

(1 citation statement)

References 52 publications

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“…An implementation clustering antibodies based on heavy-chain structural similarity (SPACE2-HC) caused a drastic decrease in clustering accuracy. This indicates that light chain structures are important for determining antibody binding specificity, which is in line with previous findings on the functional selection of light chains ( Jaffe et al, 2022 ) and their structural importance ( Guloglu and Deane, 2023 ). Similarly, combining SPACE2 with information from paratope prediction (SPACE2-Paratope) ( Chinery et al, 2023 ) and computing structural similarity only across CDRs predicted to contain paratope residues currently led to fewer functionally consistent clusters.…”

Section: Discussionsupporting

confidence: 92%

Improved computational epitope profiling using structural models identifies a broader diversity of antibodies that bind to the same epitope

Spoendlin,

Abanades,

Raybould

et al. 2023

Front. Mol. Biosci.

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The function of an antibody is intrinsically linked to the epitope it engages. Clonal clustering methods, based on sequence identity, are commonly used to group antibodies that will bind to the same epitope. However, such methods neglect the fact that antibodies with highly diverse sequences can exhibit similar binding site geometries and engage common epitopes. In a previous study, we described SPACE1, a method that structurally clustered antibodies in order to predict their epitopes. This methodology was limited by the inaccuracies and incomplete coverage of template-based modeling. In addition, it was only benchmarked at the level of domain-consistency on one virus class. Here, we present SPACE2, which uses the latest machine learning-based structure prediction technology combined with a novel clustering protocol, and benchmark it on binding data that have epitope-level resolution. On six diverse sets of antigen-specific antibodies, we demonstrate that SPACE2 accurately clusters antibodies that engage common epitopes and achieves far higher dataset coverage than clonal clustering and SPACE1. Furthermore, we show that the functionally consistent structural clusters identified by SPACE2 are even more diverse in sequence, genetic lineage, and species origin than those found by SPACE1. These results reiterate that structural data improve our ability to identify antibodies that bind to the same epitope, adding information to sequence-based methods, especially in datasets of antibodies from diverse sources. SPACE2 is openly available on GitHub (https://github.com/oxpig/SPACE2).

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Section: Discussionsupporting

confidence: 92%

Improved computational epitope profiling using structural models identifies a broader diversity of antibodies that bind to the same epitope

Spoendlin,

Abanades,

Raybould

et al. 2023

Front. Mol. Biosci.

Self Cite

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Improved computational epitope profiling using structural models identifies a broader diversity of antibodies that bind the same epitope

Spoendlin,

Abanades,

Raybould

et al. 2023

Preprint

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The function of an antibody is intrinsically linked to which epitope it engages. Clonal clustering methods, based on sequence identity, are commonly used to group antibodies that will bind the same epitope. However, such methods neglect the fact that antibodies with highly diverse sequences can exhibit similar binding site geometries and engage common epitopes. In a previous study we described SPACE1, a method that structurally clustered antibodies in order to predict their epitopes. This methodology was limited by the inaccuracies and incomplete coverage of template-based modelling. It was also only benchmarked at the level of domain-consistency on one virus class. Here, we present SPACE2, which uses the latest machine learning based structure prediction technology combined with a novel clustering protocol and benchmark it on binding data that has epitope level resolution. On six diverse sets of antigen specific antibodies we demonstrate that SPACE2 accurately clusters antibodies that engage common epitopes and achieves far higher data set coverage than clonal clustering and SPACE1. Furthermore, we show that the functionally consistent structural clusters identified by SPACE2 are even more diverse in sequence, genetic lineage, and species origin than those found by SPACE1. These results reiterate that structural data improves our ability to identify antibodies that bind the same epitope, adding information to sequence-based methods, especially in data sets of antibodies from diverse sources. SPACE2 is openly available on Github (https://github.com/oxpig/SPACE2).

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Progress and challenges in computational structure-based design and development of biologic drugs

2024

Frontiers Research Topics

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Frontiers is more than just an open access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. Frontiers journal seriesThe Frontiers journal series is a multi-tier and interdisciplinary set of openaccess, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. All Frontiers journals are driven by researchers for researchers; therefore, they constitute a service to the scholarly community. At the same time, the Frontiers journal series operates on a revolutionary invention, the tiered publishing system, initially addressing specific communities of scholars, and gradually climbing up to broader public understanding, thus serving the interests of the lay society, too. Dedication to qualityEach Frontiers article is a landmark of the highest quality, thanks to genuinely collaborative interactions between authors and review editors, who include some of the world's best academicians. Research must be certified by peers before entering a stream of knowledge that may eventually reach the public -and shape society; therefore, Frontiers only applies the most rigorous and unbiased reviews. Frontiers revolutionizes research publishing by freely delivering the most outstanding research, evaluated with no bias from both the academic and social point of view. By applying the most advanced information technologies, Frontiers is catapulting scholarly publishing into a new generation. What are Frontiers Research Topics?Frontiers Research Topics are very popular trademarks of the Frontiers journals series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area.

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Specific attributes of the V_Ldomain influence both the structure and structural variability of CDR-H3 through steric effects

Cited by 3 publications

References 52 publications

Improved computational epitope profiling using structural models identifies a broader diversity of antibodies that bind to the same epitope

Improved computational epitope profiling using structural models identifies a broader diversity of antibodies that bind to the same epitope

Improved computational epitope profiling using structural models identifies a broader diversity of antibodies that bind the same epitope

Progress and challenges in computational structure-based design and development of biologic drugs

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Specific attributes of the VLdomain influence both the structure and structural variability of CDR-H3 through steric effects

Cited by 3 publications

References 52 publications

Improved computational epitope profiling using structural models identifies a broader diversity of antibodies that bind to the same epitope

Improved computational epitope profiling using structural models identifies a broader diversity of antibodies that bind to the same epitope

Improved computational epitope profiling using structural models identifies a broader diversity of antibodies that bind the same epitope

Progress and challenges in computational structure-based design and development of biologic drugs

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Specific attributes of the V_Ldomain influence both the structure and structural variability of CDR-H3 through steric effects