A computational algorithm to assess the physiochemical determinants of T cell receptor dissociation kinetics
Zachary A Rollins1, Jun Huang2, Ilias Tagkopoulos3
1Department of Chemical Engineering.
Abstract:
The rational design of T Cell Receptors (TCRs) for immunotherapy has stagnated due to a limited understanding of the dynamic physiochemical features of the TCR that elicit an immunogenic response. The physiochemical features of the TCR-peptide major histocompatibility complex (pMHC) bond dictate bond lifetime which, in turn, correlates with immunogenicity. Here, we: i) characterize the force-dependent dissociation kinetics of the bond between a TCR and a set of pMHC ligands using Steered Molecular Dynamics (SMD); and ii) implement a machine learning algorithm to identify which physiochemical features of the TCR govern dissociation kinetics. Our results demonstrate that the total number of hydrogen bonds between the CDR2β-MHC⍺(β), CDR1α-Peptide, and CDR3β-Peptide are critical features that determine bond lifetime.
Insights
Understanding T Cell Receptor (TCR) interactions is key for immunotherapy. This study identifies critical physiochemical features, like hydrogen bonds, governing TCR-peptide major histocompatibility complex (pMHC) bond strength and lifetime.
Area of Science:
- Immunology
- Computational Biology
- Biophysics
Background:
- Rational design of T Cell Receptors (TCRs) for immunotherapy is hindered by incomplete understanding of immunogenic response drivers.
- The physiochemical characteristics of the TCR-peptide major histocompatibility complex (pMHC) bond significantly influence its lifetime and immunogenicity.
Purpose of the Study:
- To characterize the force-dependent dissociation kinetics of TCR-pMHC bonds.
- To identify key TCR physiochemical features that dictate TCR-pMHC bond lifetime using machine learning.
Main Methods:
- Steered Molecular Dynamics (SMD) simulations were employed to analyze TCR-pMHC bond dissociation kinetics.
- A machine learning algorithm was developed to correlate physiochemical features with bond dissociation dynamics.
Main Results:
- Force-dependent dissociation kinetics of TCR-pMHC bonds were successfully characterized.
- The study identified specific hydrogen bonds as critical determinants of TCR-pMHC bond lifetime.
- Key interactions include those between CDR2β-MHC⍺(β), CDR1α-Peptide, and CDR3β-Peptide.
Conclusions:
- Physiochemical features, particularly hydrogen bond networks, are critical for governing TCR-pMHC bond lifetime.
- This understanding can advance the rational design of TCR-based immunotherapies.
