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Epitope Mapping with Sidewinder: An XL-MS and Structural Modeling Approach

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Názov: Epitope Mapping with Sidewinder: An XL-MS and Structural Modeling Approach
Autori: Ströbaek, Joel, Tang, Di, Gueto-Tettay, Carlos, Gomez Toledo, Alejandro, Olofsson, Berit, Hartman, Erik, Heusel, Moritz, Malmström, Johan, Malmström, Lars
Prispievatelia: Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Infection Medicine (BMC), epIgG, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Infektionsmedicin, epIgG, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Infection Medicine (BMC), Infection Medicine Proteomics, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Infektionsmedicin, Infection Medicine Proteomics, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Infection Medicine (BMC), Quantitative immunobiology, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Infektionsmedicin, Kvantitativ immunbiologi, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Infection Medicine (BMC), Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Infektionsmedicin, Originator, Lund University, Faculty of Engineering, LTH, LTH Profile areas, LTH Profile Area: Engineering Health, Lunds universitet, Lunds Tekniska Högskola, LTH profilområden, LTH profilområde: Teknik för hälsa, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section V, Mass Spectrometry, BioMS, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion V, Masspektrometri, BioMS, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section III, Infection Medicine (BMC), SEBRA Sepsis and Bacterial Resistance Alliance, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion III, Infektionsmedicin, SEBRA Sepsis and Bacterial Resistance Alliance, Originator
Zdroj: International Journal of Molecular Sciences. 26(4):1-17
Predmety: Natural Sciences, Computer and Information Sciences, Bioinformatics (Computational Biology), Naturvetenskap, Data- och informationsvetenskap (Datateknik), Bioinformatik (Beräkningsbiologi)
Popis: Antibodies are critical to the host's immune defense against bacterial pathogens. Understanding the mechanisms of antibody-antigen interactions is essential for developing new targeted immunotherapies. Building computational workflows that can identify where an antibody binds its cognate antigen and deconvoluting the interaction interface in a high-throughput manner are critical for advancing this field. Cross-linking mass spectrometry (XL-MS) integrated with structural modeling offers a flexible and high-resolution strategy to map protein-protein interactions from low sample amounts. However, cross-linking and in silico modeling have limitations that require robust analytical workflows to make accurate inferences. In this study, we introduce Sidewinder, a modular high-throughput pipeline combining state-of-the-art computational structural prediction and molecular docking with rapid XL-MS analysis, enabling comprehensive interrogation of antibody-antigen systems. We validated this pipeline on antibodies targeting two Streptococcus pyogenes virulence factors. Using recently published data, we identified a well-defined monoclonal antibody epitope on Streptolysin O by generating and querying a large ensemble of interaction models probabilistically. We also showcased the utility of the Sidewinder pipeline by analyzing a more complex system, involving monoclonal antibodies that target the cell wall-anchored M1 protein. The flexibility and robustness of the Sidewinder pipeline provide a powerful framework for future studies of complex antibody-antigen systems, potentially leading to new therapeutic strategies.
Prístupová URL adresa: https://doi.org/10.3390/ijms26041488
Databáza: SwePub
Popis
Abstrakt:Antibodies are critical to the host's immune defense against bacterial pathogens. Understanding the mechanisms of antibody-antigen interactions is essential for developing new targeted immunotherapies. Building computational workflows that can identify where an antibody binds its cognate antigen and deconvoluting the interaction interface in a high-throughput manner are critical for advancing this field. Cross-linking mass spectrometry (XL-MS) integrated with structural modeling offers a flexible and high-resolution strategy to map protein-protein interactions from low sample amounts. However, cross-linking and in silico modeling have limitations that require robust analytical workflows to make accurate inferences. In this study, we introduce Sidewinder, a modular high-throughput pipeline combining state-of-the-art computational structural prediction and molecular docking with rapid XL-MS analysis, enabling comprehensive interrogation of antibody-antigen systems. We validated this pipeline on antibodies targeting two Streptococcus pyogenes virulence factors. Using recently published data, we identified a well-defined monoclonal antibody epitope on Streptolysin O by generating and querying a large ensemble of interaction models probabilistically. We also showcased the utility of the Sidewinder pipeline by analyzing a more complex system, involving monoclonal antibodies that target the cell wall-anchored M1 protein. The flexibility and robustness of the Sidewinder pipeline provide a powerful framework for future studies of complex antibody-antigen systems, potentially leading to new therapeutic strategies.
ISSN:14220067
DOI:10.3390/ijms26041488