Computational Antibody Papers

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molecular dynamics
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2024
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  • 2024-05-29

    Deciphering deamidation and isomerization in therapeutic proteins: Effect of neighboring residue

    • liabilities
    • molecular dynamics
    • quantum
    • Authors perform simulations of structure to create a classifier of ASP/ASN degradation.
    • They use the Adimab database of 131 therapeutics where degradation rates were studied.
    • They look at three metrics: D1) backbone dihedral conformation of the n + 1 residue, (D2) side-chain dihedral conformation of Asn/Asp residue, (D3) fraction of time the Asn/Asp residue remains solvent accessible.
    • The combined model achieves accuracy of around ~.85
    • The best accuracy is achieved on the backbone (D1) model, indicating that this might be the most important descriptor.
    • Citing the Adimab study: for instance, there were 27 deamidation sites with the hotspot NG sequence in the complementary-determining region (CDR), of which only 14 underwent deamidation. A similar trend was observed in the case of isomerization (16 of 44 DG sites isomerized).
    • They study the ASN/ASP degradation (isomerisation and deamidation) by looking at the proton affinity
    • Backbone secondary structure, side-chain rotamer conformation and solvent accessibility were found to be key molecular indicators of Asp isomerization and Asn deamidation