Role of the n + 1 amino acid residue on the deamidation of asparagine in pentapeptides

Deamidation plays an important role in biochemical phenomena such as aging. The role of the n + 1 residue on the deamidation of asparagine (asparagine being the nth residue) in three pentapeptide chains (GGNGG, GGNMG and GGNIG) has been analysed with hybrid computational tools. Potentials of mean force at 300 K were calculated from the MD/replica exchange simulations using weighted histogram analysis (WHAM) in explicit water. The snapshots were clustered taking into account the requirements of the plausible deamidation mechanisms, as such the tautomerisation of the asparagine side chain as initial step has been confirmed, based on the proximity of water to the deamidation site. The ultimate goal being to gain an insight on the peptide backbone N-H acidity, quantum mechanical calculations have been carried out. For this purpose, the distribution of Φ/Ψ, Φ₂/Ψ and end-to-end distances deduced from the WHAM diagrams have been considered and a total of 110 structures have been sampled. These neutral pentapeptides as well as their corresponding anions have been optimised (B3LYP/6-31++G(d,p)) in implicit water in order to gain an insight on the peptide backbone N-H acidity. In this study, we have shown that the open conformations of the neutrals and the anions, which display a β sheet like structure are well populated and their pK_as rank in the same order as the deamidating half-lives, that is the peptides that deaminate fastest can more readily access conformations that are more acidic.