A density functional theory study on peptide bond cleavage at aspartic residues: direct vs cyclic intermediate hydrolysis

Abstract

In this work, peptide bond cleavages at carboxy- and amino-sides of the aspartic residue in a peptide model via direct (concerted and step-wise) and cyclic intermediate hydrolysis reaction pathways were explored computationally. The energetics, thermodynamic properties, rate constants, and equilibrium constants of all hydrolysis reactions, as well as their energy profiles were computed at the B3LYP/6-311++G(d,p) level of theory. The result indicated that peptide bond cleavage of the Asp residue occurred most preferentially via the cyclic intermediate hydrolysis pathway. In all reaction pathways, cleavage of the peptide bond at the amino-side occurred less preferentially than at the carboxy-side. The overall reaction rate constants of peptide bond cleavage of the Asp residue at the carboxy-side for the assisted system were, in increasing order: concerted < step-wise < cyclic intermediate.

Experimental and computational analysis of 1-(4-chloro-3-nitrophenyl)-3-(3,4-dichlorophenyl)thiourea

“…To investigate sensitivity of CNDCT as a drug candidate molecule towards degradation, we have calculated BDE and RDFs. Calculations of BDE may provide information on molecule site that is prone to autoxidation mechanism, while calculations of RDF may provide information on atoms with high interactions with water molecules and therefore sensitivity towards hydrolysis mechanism [93][94][95][96]. Only at certain molecule sites hydrogen atoms can be abstracted and autoxidation can take part.…”

4-[(4-acetylphenyl)amino]-2-methylidene-4-oxobutanoic acid, a newly synthesized amide with hydrophilic and hydrophobic segments: Spectroscopic characterization and investigation of its reactive properties

“…confirmation of the degradation path of some organic pharmaceutical molecules could be assessed by calculations of the BDE for hydrogen abstraction. [62][63][64][65][66][67][68][69][70][71][72][73][74][75] A molecule is considered suitable for an autoxidation mechanism when the BDE values are in the appropriate range. If the BDE values fall in the range between 75 to 85 kcal mol -1 , 76,77 the molecule could be considered as very sensitive to an autoxidation mechanism.…”

Supramolecular architecture of 5-bromo-7-methoxy-1-methyl-1H-benzoimidazole.3H2O: Synthesis, spectroscopic investigations, DFT computation, MD simulations and docking studies

“…Computational molecular modelling based on the DFT calculations and MD simulations is very important for the environmental studies [80][81][82][83], especially when it comes to the oxidation reactions, which are essential for the degradation and removal of the pharmaceutical pollutants from water resources [84][85][86]. In order to evaluate sensitivity of molecule towards the autoxidation mechanism, calculations of bond dissociation energies for hydrogen abstraction (H-BDE) could be particularly useful.…”