Abstract
Deamidation of asparagine (Asn) residues is a nonenzymatic post-translational modification of proteins. Asn deamidation is associated with pathogenesis of age-related diseases and hypofunction of monoclonal antibodies. Deamidation rate is known to be affected by the residue following Asn on the carboxyl side and by secondary structure. Information about main-chain conformation of Asn residues is necessary to accurately predict deamidation rate. In this study, the effect of main-chain conformation of Asn residues on deamidation rate was computationally investigated using molecular dynamics (MD) simulations and quantum chemical calculations. The results of MD simulations for γS-crystallin suggested that frequently deamidated Asn residues have common main-chain conformations on the N-terminal side. Based on the simulated structure, initial structures for the quantum chemical calculations were constructed and optimized geometries were obtained using the B3LYP density functional method. Structures that were frequently deamidated had a lower activation energy barrier than that of the little deamidated structure. We also showed that dihydrogen phosphate and bicarbonate ions are important catalysts for deamidation of Asn residues.
Highlights
Deamidation of asparagine (Asn) residue is a post-translational modification observed in various proteins and has been reported to spontaneously and nonenzymatically occur in vivo and in vitro under physiological conditions [1,2,3,4,5,6]
We focused on the 3D structure of γS-crystallin, which is targeted for deamidation amidation rate
molecular dynamics (MD) simulations and quantum chemical calculations demonstrated that Asn deamidation more occurs in the syn conformation than in the anti conformation
Summary
Deamidation of asparagine (Asn) residue is a post-translational modification observed in various proteins and has been reported to spontaneously and nonenzymatically occur in vivo and in vitro under physiological conditions [1,2,3,4,5,6]. This reaction typically proceeds through the cyclic succinimide intermediate, resulting in the production of Asp and biologically uncommon isoAsp residues in an approximately 1:3 molar ratio (Figure 1) [7]. Because deamidation can result in protein denaturation and aggregation, it is suggested to trigger several age-related diseases [14,15,16,17,18]
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