Computational Characterization of N-acetylaspartylglutamate Synthetase: From the Protein Primary Sequence to Plausible Catalytic Mechanism




molecular dynamics, quantum mechanics/molecular mechanics, QM/MM MD, GPU-accelerated algorithms, N-acetylaspartylglutamate synthetase, enzyme-substrate complexes, reaction intermediates


The methods of supercomputer molecular modeling are applied to characterize structure and dynamics of one of the key human brain enzymes, N-acetylaspartylglutamate synthetase. The three-dimensional all-atom models of the enzyme with the reactants in the active site are constructed in several steps, starting from pilot protein structure in the apo-form obtained with the AlphaFold2 from the protein primary sequence. Deposition of reactant molecules into the protein cavity, construction of the reaction intermediate and relaxation of the complex are carried out with the help of large-scale classical molecular dynamics calculations. On the top of the construct, molecular dynamics simulations with the quantum mechanics/molecular mechanics interaction potentials are performed for the most promising conformations of the model system. Analysis of the latter allows us to propose plausible catalytic mechanisms of chemical reactions in the enzyme active site. The applied computational strategy opens the way towards ab initio enzymology using modern supercomputer simulations.


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How to Cite

Polyakov, I. V., Kniga, A. E., & Nemukhin, A. V. (2022). Computational Characterization of N-acetylaspartylglutamate Synthetase: From the Protein Primary Sequence to Plausible Catalytic Mechanism. Supercomputing Frontiers and Innovations, 9(2), 4–13.

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