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

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.