The deamidation reaction in the enzyme Triosephosphate isomerase (TPI) is investigated by means of molecular dynamics. Simulations based on the classical AMBER force field are performed in 60 to 90 ns timescale for six distinct samples: wild-type protein extracted from crystallographic structure, substrate-bound system; structures to represent closed and open states of TPI; mutated simulations where the asparagine of the primary deamidation site has been replaced by aspartate residue on each TPI monomer. By using the NAC analysis, we have found that only two initiations of the deamidation reaction seem possible in TPI: 1) a mechanism starting with the tautomerization of Asn side chain assisted by two water molecules; 2) a mechanism involving the direct formation of the tetrahedral intermediate. Comparison with the Gly-Gly-Asn-Gly-Gly pentapeptide shows that NAC probabilities related to the tautomerization reaction as well as the tetrahedral intermediate formation are similar for TPI and the pentapeptide.

Modeling the deamidation in peptides and TPI

244th National Meeting (2012)

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