Using molecular dynamics simulations to interrogate T cell receptor non-equilibrium kinetics.

Area of Science:

• Immunology
• Computational Biology
• Biophysics

Background:

• T Cell Receptor (TCR) recognition of peptide-major histocompatibility complex (pMHC) is crucial for adaptive immunity.
• Mechanosensing by TCRs involves detecting mechanical forces exerted on the pMHC complex.
• Understanding TCR-pMHC interactions at an atomic scale can guide the development of targeted immunotherapies.

Purpose of the Study:

• To elucidate the atomic-scale mechanism of TCR mechanosensing of peptides within the pMHC binding groove.
• To investigate how peptide mutations influence pMHC conformation and TCR-pMHC bond dynamics.
• To correlate physiochemical bond features with T cell immunogenic responses for immunotherapy design.

Main Methods:

• Utilized steered molecular dynamics (SMD) simulations to model TCR-pMHC interactions under load.
• Analyzed equilibrium pMHC conformation changes in response to peptide mutations.
• Quantified TCR-pMHC bond strength (duration and length) and identified key physiochemical interactions (hydrogen bonds, Lennard-Jones contacts).

Main Results:

• Peptide mutations within the pMHC binding groove alter the equilibrium MHC conformation.
• These conformational changes directly impact the overall strength and duration of the TCR-pMHC bond under constant force.
• Specific physiochemical features of the dynamic TCR-pMHC bond strength correlate with the immunogenicity of the presented peptide.

Conclusions:

• Transient TCR-pMHC bond formation is a hallmark of immunogenic peptides.
• Steered molecular dynamics simulations provide valuable insights into TCR-pMHC interactions.
• This study offers a framework for designing novel TCRs for enhanced immunotherapeutic strategies.