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On the Mechanism and Rate of Spontaneous Decomposition of Amino Acids

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Anastassia N. Alexandrova*† and William L. Jorgensen‡

Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United States

Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States

J. Phys. Chem. B, 2011, 115 (46), pp 13624–13632

DOI: 10.1021/jp2081808

Publication Date (Web): October 14, 2011

E-mail: ana@chem.ucla.edu.

Section:

Physical Organic Chemistry

Abstract

Spontaneous decarboxylation of amino acids is among the slowest known reactions; it is much less facile than the cleavage of amide bonds in polypeptides. Establishment of the kinetics and mechanisms for this fundamental reaction is important for gauging the proficiency of enzymes. In the present study, multiple mechanisms for glycine decomposition in water are explored using QM/MM Monte Carlo simulations and free energy perturbation theory. Simple CO₂ detachment emerges as the preferred pathway for decarboxylation; it is followed by water-assisted proton transfer to yield the products: CO₂ and methylamine. The computed free energy of activation of 45 kcal/mol, and the resulting rate-constant of 1 × 10^–21 s^–1, can be compared with an extrapolated experimental rate constant of 2 × 10^–17 s^–1 at 25 °C. The half-life for the reaction is more than 1 billion years. Furthermore, examination of deamination finds simple NH₃-detachment yielding α-lactone to be the favored route, though it is less facile than decarboxylation by 6 kcal/mol. Ab initio and DFT calculations with the CPCM hydration model were also carried out for the reactions; the computed free energies of activation for glycine decarboxylation agree with the QM/MM result, whereas deamination is predicted to be more favorable. QM/MM calculations were also performed for decarboxylation of alanine; the computed barrier is 2 kcal/mol higher than for glycine in qualitative accord with experiment.