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SnugDock: Paratope Structural Optimization during Antibody-Antigen Docking Compensates for Errors in Antibody Homology Models

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  • Aroop Sircar
  • Jeffrey J Gray

Abstract

High resolution structures of antibody-antigen complexes are useful for analyzing the binding interface and to make rational choices for antibody engineering. When a crystallographic structure of a complex is unavailable, the structure must be predicted using computational tools. In this work, we illustrate a novel approach, named SnugDock, to predict high-resolution antibody-antigen complex structures by simultaneously structurally optimizing the antibody-antigen rigid-body positions, the relative orientation of the antibody light and heavy chains, and the conformations of the six complementarity determining region loops. This approach is especially useful when the crystal structure of the antibody is not available, requiring allowances for inaccuracies in an antibody homology model which would otherwise frustrate rigid-backbone docking predictions. Local docking using SnugDock with the lowest-energy RosettaAntibody homology model produced more accurate predictions than standard rigid-body docking. SnugDock can be combined with ensemble docking to mimic conformer selection and induced fit resulting in increased sampling of diverse antibody conformations. The combined algorithm produced four medium (Critical Assessment of PRediction of Interactions-CAPRI rating) and seven acceptable lowest-interface-energy predictions in a test set of fifteen complexes. Structural analysis shows that diverse paratope conformations are sampled, but docked paratope backbones are not necessarily closer to the crystal structure conformations than the starting homology models. The accuracy of SnugDock predictions suggests a new genre of general docking algorithms with flexible binding interfaces targeted towards making homology models useful for further high-resolution predictions.Author Summary: Antibodies are proteins that are key elements of the immune system and increasingly used as drugs. Antibodies bind tightly and specifically to antigens to block their activity or to mark them for destruction. Three-dimensional structures of the antibody-antigen complexes are useful for understanding their mechanism and for designing improved antibody drugs. Experimental determination of structures is laborious and not always possible, so we have developed tools to predict structures of antibody-antigen complexes computationally. Computer-predicted models of antibodies, or homology models, typically have errors which can frustrate algorithms for prediction of protein-protein interfaces (docking), and result in incorrect predictions. Here, we have created and tested a new docking algorithm which incorporates flexibility to overcome structural errors in the antibody structural model. The algorithm allows both intramolecular and interfacial flexibility in the antibody during docking, resulting in improved accuracy approaching that when using experimentally determined antibody structures. Structural analysis of the predicted binding region of the complex will enable the protein engineer to make rational choices for better antibody drug designs.

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  • Aroop Sircar & Jeffrey J Gray, 2010. "SnugDock: Paratope Structural Optimization during Antibody-Antigen Docking Compensates for Errors in Antibody Homology Models," PLOS Computational Biology, Public Library of Science, vol. 6(1), pages 1-13, January.
  • Handle: RePEc:plo:pcbi00:1000644
    DOI: 10.1371/journal.pcbi.1000644
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    1. Grant E. Nybakken & Theodore Oliphant & Syd Johnson & Stephen Burke & Michael S. Diamond & Daved H. Fremont, 2005. "Structural basis of West Nile virus neutralization by a therapeutic antibody," Nature, Nature, vol. 437(7059), pages 764-769, September.
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    1. Thillai V. Sekar & Eslam A. Elghonaimy & Katy L. Swancutt & Sebastian Diegeler & Isaac Gonzalez & Cassandra Hamilton & Peter Q. Leung & Jens Meiler & Cristina E. Martina & Michael Whitney & Todd A. Ag, 2023. "Simultaneous selection of nanobodies for accessible epitopes on immune cells in the tumor microenvironment," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Massih Khorvash & Nick Blinov & Carol Ladner-Keay & Jie Lu & Judith M Silverman & Ebrima Gibbs & Yu Tian Wang & Andriy Kovalenko & David Wishart & Neil R Cashman, 2020. "Molecular interactions between monoclonal oligomer-specific antibody 5E3 and its amyloid beta cognates," PLOS ONE, Public Library of Science, vol. 15(5), pages 1-35, May.
    3. Jordan R Willis & Bryan S Briney & Samuel L DeLuca & James E Crowe Jr & Jens Meiler, 2013. "Human Germline Antibody Gene Segments Encode Polyspecific Antibodies," PLOS Computational Biology, Public Library of Science, vol. 9(4), pages 1-14, April.
    4. Haohuai He & Bing He & Lei Guan & Yu Zhao & Feng Jiang & Guanxing Chen & Qingge Zhu & Calvin Yu-Chian Chen & Ting Li & Jianhua Yao, 2024. "De novo generation of SARS-CoV-2 antibody CDRH3 with a pre-trained generative large language model," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Jeffrey A. Ruffolo & Lee-Shin Chu & Sai Pooja Mahajan & Jeffrey J. Gray, 2023. "Fast, accurate antibody structure prediction from deep learning on massive set of natural antibodies," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Julia Koehler Leman & Sergey Lyskov & Steven M. Lewis & Jared Adolf-Bryfogle & Rebecca F. Alford & Kyle Barlow & Ziv Ben-Aharon & Daniel Farrell & Jason Fell & William A. Hansen & Ameya Harmalkar & Je, 2021. "Ensuring scientific reproducibility in bio-macromolecular modeling via extensive, automated benchmarks," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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