The reaction mechanism for the hydrolysis of amide bonds is a much debated topic in literature. This is not surprising when considering the variety of biologically significant domains in which this reaction is of interest, ranging from peptide bonds to protein side chain degradation. For instance, asparagine (Asn) and glutamine (Gln) residues are known to undergo spontaneous nonenzymatic deamidation in water to form aspartic acid and glutamic acid residues under physiological conditions. Deamidation could be the result of a hydrolysis reaction, either via a concerted or a stepwise mechanism.
Gas phase calculations have shown that explicit water molecules play an important role in this reaction, but to date, no simulations of hydrolysis pathways using a periodic water model have been performed.
In this work, we perform quantum mechanical metadynamics simulations on the hydrolysis of acetamide as a model compound for Asn or Gln. The periodic simulation cell consists of one acetamide molecule and 90 water molecules in a cubic 15 Å box.
From all previously suggested pathways and a new, alternative route, the most competitive pathway can be identified. These results give a clearer insight in deamidation processes proteins and polypeptides and show that an adequate description of the natural surroundings the active species is necessary for obtaining a realistic image of biological processes
