Uncovering the flexibility of CDR loops in antibodies and TCRs through large-scale molecular dynamics

2025/11/12 by Matteo Cagiada, Fabian C. Spoendlin, King Ifashe +1 · 1 voice · 1 citation
Medicine · Biochemistry, Genetics and Molecular Biology · #Monoclonal and Polyclonal Antibodies Research #Protein Structure and Dynamics #vaccines and immunoinformatics approaches

paper · doi:10.1101/2025.11.10.687725

openalex publication_date 2025/11/12 · openalex created_date 2025/11/12 · openalex updated_date 2026/07/15

Abstract

Abstract Antibody structures are composed of framework regions that adopt a conserved fold and complementarity determining regions (CDR) loops which are far more variable. Flexibility of CDR loops has been linked to key properties such as affinity and specificity. However, owing to the scarcity of available data it has not been possible to study the functional implications of their dynamics in detail. To overcome these data limitations, we introduce CALVADOS 3-Fv, a customised set-up of the residue-based CALVADOS 3 model, utilizing restraints and parameterization tailored for immune receptor simulations. CALVADOS 3-Fv reproduces ensemble metrics in all atom simulations and experimental data with high accuracy. Having validated our protocol, we created FlAbDab and FTCRDab, two databases containing simulations of more than 150,000 antibodies and T-cell receptors. The databases are released open source to enable the study of CDR dynamics and as a large data source for training machine learning models.

Citations

• Characterizing the Diversity of the CDR-H3 Loop Conformational Ensembles in Relationship to Antibody Binding Properties
• Highly accurate protein structure prediction with AlphaFold
• AmberTools
• Conformational ensembles of the human intrinsically disordered proteome
• Learning to engineer protein flexibility
• AF-CALVADOS: AlphaFold-guided simulations of multi-domain proteins at the proteome level

Cited by

• Spatial Compartmentalization of TCR Repertoires Between Primary Melanomas and Sentinel Lymph Nodes Reveals Distinct Clonal Architectures and Shared Antigen Recognition

Discussions

• Find all the details and links to the databases in the preprint manuscript (doi.org/10.1101/2025...) [bsky, 3 points, 1 comments]

Related

• FlAbDab & TCRDab: Large-Scale MD Simulations of experimentally resolved Antibody and TCR Fv regions (Cagiada M, Spoendlin F.C - 2025)
• Characterizing the Diversity of the CDR-H3 Loop Conformational Ensembles in Relationship to Antibody Binding Properties
• AntibodyFlow: Normalizing Flow Model for Designing Antibody Complementarity-Determining Regions
• ABodyBuilder3: Improved and scalable antibody structure predictions
• Simple End-to-end Deep Learning Model for CDR-H3 Loop Structure Prediction