A DFT calculation on nonenzymatic degradation of isoaspartic residue

βAsp is an isomer of Asp that can be formed by either deamidation of Asn or isomerization of Asp and known as biological clock. The presence of βAsp affects the proteolytic stability of the protein. Formation of the isomerized Asp plays a diverse and crucial role in aging, cancer, autoimmune, neurodegenerative, and other diseases. A number of methods have been developed to detect βAsp, and they are usually used in conjunction. Because of identical mass, differentiation of βAsp and Asp residues is challenged. Degradation of βAsp is still unclear and needed to be explored. The energetics and mechanism of five possible pathways for cleavages at βAsp in peptide model have been investigated by DFT/B3LYP/6-311 +  + G(d,p) level of the theory. The calculations show that peptide bond cleavage at α-chain (amino side) due to αO_C → αC_N ring closure is the most favorable reaction. The result is in agreement with experiment utilizing PSD/CRF method. The second most favorable pathway is due to αO_C → βC ring closure results in β-chain cleavage. The cleavage products βAsp and Asp fragments can be used to signify an abundance of βAsp residue in nonenzymatic condition. Other three cyclizations initiated by either α- or β-amino nitrogen result in various cleavages, isomerization to Asp, and reconversion to original βAsp. These three cyclization pathways are obstructed because they require mostly high activation barriers and their intermediates are quite less thermodynamically stable. Thus, computational results also confirm that βAsp → Asp is prohibited in case of nonenzymatic condition which means that protein L-isoaspartyl O-methyl transferase (PIMT) is needed for this modification.