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bioRxiv · 10.1101/2021.07.26.453885

Divining Deamidation and Isomerization in Therapeutic Proteins: Effect of Neighboring Residue

Irudayanathan, F. J.·Zarzar, J.·Lin, J.·Izadi, S.
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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 sequences propensity for such PTMs can help expedite protein therapeutic discovery and development. In this study, we utilized proton-affinity calculations with semi-empirical quantum mechanics (QM) and {micro}s long equilibrium molecular dynamics (MD) simulations to investigate mechanistic roles of structure and chemical environment in dictating spontaneous degradation of asparagine and aspartic acid residues in 131 clinical-stage therapeutic antibodies. Backbone secondary structure, side-chain rotamer conformation and solvent accessibility were found as three 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 ASP/ASN degradation. With these findings, we propose a minimalistic physics-based classification model that can be leveraged to predict deamidation and isomerization propensity of therapeutic proteins.

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Irudayanathan, F. J., Zarzar, J., Lin, J., Izadi, S.. 2021-07-26. Divining Deamidation and Isomerization in Therapeutic Proteins: Effect of Neighboring Residue. https://doi.org/10.1101/2021.07.26.453885

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