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Biochemistry. 2006 Apr 25;45(16):5384-92.

Asparagine deamidation: pH-dependent mechanism from density functional theory.

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  • 1Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.


Asparagine deamidation is a decisive event in chemotherapy-induced apoptosis and a major obstacle in the formulation of monoclonal antibodies. Despite the importance of deamidation, little is known about the elementary reactions involved. B3LYP/6-31+G(d,p)/COSMO-RS calculations were used to obtain stable structures and transition states for a network of reactions. Calculated rate constants were incorporated into a kinetic model of the pH dependence and compared to a pseudo-steady-state model. At low pH, the calculations show that deamidation occurs by direct acid-catalyzed hydrolysis to aspartate. At neutral to basic pH, deamidation proceeds by the initial formation of a tetrahedral intermediate. The intermediate can be converted to succinimide by two pathways and three rate-determining steps that shift in relative importance with pH. The calculated pH-dependent rate constant qualitatively agrees with the experimental pH dependence. The rate-determining transition state structures may help to understand chemotherapy-induced apoptosis and improve protein formulations.

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