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Reliable In Silico ...
Reliable In Silico Ranking of Engineered Therapeutic TCR Binding Affinities with MMPB/GBSA
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- Crean, Rory M. (author)
- Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England; Univ Bath, Doctoral Training Ctr Sustainable Chem Technol, Bath BA2 7AY, Avon, England
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- Pudney, Christopher R. (author)
- Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England.;Univ Bath, Ctr Therapeut Innovat, Bath BA2 7AY, Avon, England.
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- Cole, David K. (author)
- Immunocore Ltd, Abingdon OX14 4RY, Oxon, England.;Cardiff Univ, Div Infect & Immun, Cardiff CF14 4XN, Wales.
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- van der Kamp, Marc W. (author)
- Univ Bristol, Sch Biochem, Bristol BS8 1TD, Avon, England.
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Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England; Univ Bath, Doctoral Training Ctr Sustainable Chem Technol, Bath BA2 7AY, Avon, England Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England;Univ Bath, Ctr Therapeut Innovat, Bath BA2 7AY, Avon, England. (creator_code:org_t)
- 2022-01-20
- 2022
- English.
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In: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 62:3, s. 577-590
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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