Reliable In Silico Ranking of Engineered Therapeutic TCR Binding Affinities with MMPB/GBSA

• Published in: Journal of chemical information and modeling 2022-02, Vol.62 (3), p.577-590
• Main Authors: Crean, Rory M., Pudney, Christopher R., Cole, David K., van der Kamp, Marc W.
• Format: Article
• Language: English
• Subjects: Affinity; Antigens; Binding; Computational Biochemistry; Entropy; Humans; Leukocytes; Ligands; Molecular dynamics; Molecular Dynamics Simulation; Mutation; Optimization; Protein Binding; Proteins; Proteins - chemistry; Ranking
• ISSN: 1549-9596; 1549-960X; 1549-960X
• DOI: 10.1021/acs.jcim.1c00765

Accurate and efficient in silico ranking of protein–protein binding affinities is useful for protein design with applications in biological therapeutics. One popular approach to rank binding affinities is to apply the molecular mechanics Poisson–Boltzmann/generalized Born surface area (MMPB/GBSA) method to molecular dynamics (MD) trajectories. Here, we identify protocols that enable the reliable evaluation of T-cell receptor (TCR) variants binding to their target, peptide-human leukocyte antigens (pHLAs). We suggest different protocols for variant sets with a few (≤4) or many mutations, with entropy corrections important for the latter. We demonstrate how potential outliers could be identified in advance and that just 5–10 replicas of short (4 ns) MD simulations may be sufficient for the reproducible and accurate ranking of TCR variants. The protocols developed here can be applied toward in silico screening during the optimization of therapeutic TCRs, potentially reducing both the cost and time taken for biologic development.