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

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

SUBMITTER: Irudayanathan FJ 

PROVIDER: S-EPMC9673968 | biostudies-literature | 2022 Jan-Dec

REPOSITORIES: biostudies-literature