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

Abstract

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.

Keywords:

• deamidation
• peptide
• modelling

Acknowledgements

We thank Prof. Gerald Monard (Université de Lorraine, France) for fruitful discussions and also Şeref Gül (Koc University, Turkey) for the generation of some of the simulation data presented here. The computational resources used in this work were provided by the TUBITAK ULAKBIM High Performance and Grid Computing Center under the grant number 113Z210 and the project DPT-2009K120520. The Boğaziçi University research grants under the project number 556 are gratefully acknowledged.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplemental data

Supplemental data for this article can be accessed http://10.1080/00268976.2015.1068394.

Additional information

Funding

TUBITAK (grant number 113Z210), ULAKBIM High Performance and Grid Computing Center, DPT (grant number 2009K120520) and Boğaziçi University (grant number 556).