ИСТИНА

Recent results [1-3] of modeling chemical transformations in enzyme active sites using quantum-based approaches will be discussed. We apply quantum mechanics/molecular mechanics (QM/MM) approaches to compute minimum energy pathways connecting enzyme-substrate and enzyme-product complexes. Appropriate crystal structures from the Protein Data Bank usually serve as a source of coordinates of heavy atoms to create molecular model systems. After in silico construction of a three-dimensional full-atom model, evolution of the model system along carefully selected reaction coordinates is analyzed. Several examples of such modeling will be presented. The complete cycle of chemical transformations in penicillin acylase, a unique enzyme that belongs to the recently discovered superfamily of N-terminal nucleophile hydrolases, with its most specific substrate, penicillin G, leading to formation of 6-aminopenicillanic and phenylacetic acids [1] will be presented. Keton-ketal transformations at the active site of matrix metalloproteinases characterized computationally [2] may be explored to propose specific inhibitors. Chemical reactions in photoreceptor proteins constitute an active field of application of QM/MM modeling; the case of BLUF domains will be discussed [3]. Simulation results of guanosine triphposphate hydrolysis (GTP) by small GTPases, icluding Ras protein, will be in focus. According to newly obtained data, the molecular events of the chemical steps upon GTP hydrolysis include: (i) cleavage of the phosphorus (Pγ) -oxygen bond in GTP upon approach of the properly aligned catalytic water molecule, producing GDP; (ii) formation of a new chemical bond between phosphorus and oxygen of water; (iii) redistribution of protons between reacting species leading to inorganic phosphate Pi. References [1] Grigorenko B.L., Khrenova M.G., Nilov D.K., Nemukhin A.V., Švedas V.K. Catalytic Cycle of Penicillin Acylase from Escherichia coli: QM/MM Modeling of Chemical Transformations in the Enzyme Active Site upon Penicillin G Hydrolysis // ACS Catal. 2014. V. 4. P. 2521–2529. [2] Khrenova M.G., Nemukhin A.V., Savitsky A.P. Computational Characterization of Ketone-Ketal Transformations at the Active Site of Matrix Metalloproteinases // J. Phys. Chem. B. 2014. V. 118. P. 4345-4350. [3] Khrenova M.G., Nemukhin A.V., Domratcheva T. Photoinduced Electron Transfer Facilitates Tautomerization of the Conserved Signaling Glutamine Side Chain in BLUF Protein Light Sensors // J. Phys. Chem. B. 2013 V. 117. P. 2369-2377.