Scherlo, Marvin and Hoeveler, Adrian and Mann, Marvin and Gerwert, Grischa and Gueldenhaupt, Joern and Gerwert, Klaus and Rudack, Till and Koetting, Carsten (2025) Replacement of a single residue in an antibody abolishes cognate antigen binding, as predicted by theoretical methods. COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL, 27. pp. 4363-4372. ISSN 2001-0370,
Full text not available from this repository. (Request a copy)Abstract
Structural insights into the interaction between antibodies and antigens at the atomic level are pivotal for understanding the molecular mechanisms of antigen binding. Despite the availability of structural models generated by recent artificial intelligence advancements, computational predictions require experimental validation to confirm their accuracy. Here, we demonstrate an approach that combines computational protein modeling with spectroscopic experiments to validate antibody-antigen interactions. As a case example we use solanezumab, a monoclonal antibody that targets amyloid-beta (A beta), whose misfolding is the main factor responsible for Alzheimer's disease. For this antibody, we predicted a single mutation, G95AHC, within the paratope of the heavy chain to disrupt antigen binding. This mutation, referred to as a "dead mutant", was experimentally validated using an immuno-infrared biosensor (iRS). Our results confirmed that the mutation abolished antigen binding without affecting the native structure of the antibody. The use of dead mutants enables precise differentiation between specific and nonspecific binding, which is particularly important in medical diagnostics. We applied this approach to analyze the binding of solanezumab to synthetically produced A beta variants and A beta catched by the iRS functionalized surface from cerebrospinal fluid, showcasing its utility in Alzheimer's disease diagnostics. These findings highlight the value of computational modeling and experimental validation in understanding antigen-antibody interactions, with significant implications for diagnostic and therapeutic applications.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MOLECULAR-DYNAMICS; SECONDARY STRUCTURE; ALZHEIMERS-DISEASE; DNASE DOMAIN; COLICIN E7; ALGORITHM; COMPLEX; PEPTIDE; Antibody-Antigen-Interaction; Mutagenesis; Protein Modeling; ATR-FTIRSpectroscopy; Immuno Infrared Sensor; Molecular dynamics simulations; Solanezumab; Amyloid-Beta; Alzheimer |
| Subjects: | 000 Computer science, information & general works > 004 Computer science 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie > Prof. Dr. Till Rudack Regensburg Center for UltrafastNanoscopy (RUN) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 May 2026 06:52 |
| Last Modified: | 06 May 2026 06:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/66153 |
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