ArticlemAbs
Deciphering deamidation and isomerization in therapeutic proteins: Effect of neighboring residue.
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Who cites it
16 citing papers in PubMed, 31 citations in OpenAlex.
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- Engineered MspA Nanopores for Real-Time Detection of Insulin, Its Pharmaceutical Analogues, and Degradation Products.ACS nano · 2026Article
- Insights into the role of internal catalysts in asparagine-to-succinimide conversion in a hyperthermophilic glutamine amidotransferase.The Journal of biological chemistry · 2026Article
- Integrative Peptide Drug Development: Chemical Engineering, AI-Driven Design, and Cell-Penetrating Peptides.Pharmaceutics · 2026Review
- Developability Evaluation of Single-Domain Antibody-Chelator Conjugates for Diagnostic Radiotracers.Antibodies (Basel, Switzerland) · 2026Article
- Effect of Copper-Catalyzed Oxidation on the Aggregation of the Islet Amyloid Polypeptide.Antioxidants (Basel, Switzerland) · 2025Article
- Mechanism-Driven Features Enable Asn Deamidation Reactivity Prediction via Machine Learning Methods.Journal of chemical information and modeling · 2025Article
- Advances in the Study of Protein Deamidation: Unveiling Its Influence on Aging, Disease Progression, Forensics and Therapeutic Efficacy.Proteomes · 2025Review
- LAP: Liability Antibody Profiler by sequence & structural mapping of natural and therapeutic antibodies.PLoS computational biology · 2024Article
- Combining machine learning with structure-based protein design to predict and engineer post-translational modifications of proteins.PLoS computational biology · 2024Article
- Molecular Modeling of the Deamidation Reaction in Solution: A Theoretical-Computational Study.The journal of physical chemistry. B · 2023Article
- How can we discover developable antibody-based biotherapeutics?Frontiers in molecular biosciences · 2023Review
- Structural modeling of antibody variable regions using deep learning-progress and perspectives on drug discovery.Frontiers in molecular biosciences · 2023Review
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Corrections and comments
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Deamidation of asparagine (Asn) and isomerization of aspartic acid (Asp) residues are among the most commonly observed spontaneous post-translational modifications (PTMs) in proteins. Understanding and predicting a protein sequence's propensity for such PTMs can help expedite protein therapeutic discovery and development. In this study, we used proton-affinity calculations with semi-empirical quantum mechanics and microsecond long equilibrium molecular dynamics simulations to investigate mechanistic roles of structural conformation and chemical environment in dictating spontaneous degradation of Asn and Asp residues in 131 clinical-stage therapeutic antibodies. Backbone secondary structure, side-chain rotamer conformation and solvent accessibility were found to be key molecular indicators of Asp isomerization and Asn deamidation. Comparative analysis of backbone dihedral angles along with N-H proton affinity calculations provides a mechanistic explanation for the strong influence of the identity of the n + 1 residue on the rate of Asn/Asp degradation. With these findings, we propose a minimalistic physics-based classification model that can be leveraged to predict deamidation and isomerization propensity of proteins.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.