Journal article
Water-Intake and Water-Molecule Paths to the Active Site of Secretory Phospholipase A2 Studied Using MD Simulations and the Tracking Tool AQUA-DUCT
Secretory phospholipases A2 (sPLA2s) are a subclass of enzymes that catalyze the hydrolysis at the sn-2 position of glycerophospholipids, producing free fatty acids and lysophospholipids. In this study, different phospholipids with structural modifications close to the scissile sn-2 ester bond were studied to determine the effect of the structural changes on the formation of the Michaelis-Menten complex and the water entry/exit pathways using molecular dynamics simulations and the computational tracking tool AQUA-DUCT.
Structural modifications include methylation, dehydrogenation, and polarization close to the sn-2 scissile bond. We found that all water molecules reaching the active site of sPLA2-IIA pass by the aromatic residues Phe5 and Tyr51 and enter the active site through an active-site cleft. The relative amount of water available for the enzymatic reaction of the different phospholipid-sPLA2 complexes was determined together with the distance between key atoms in the catalytic machinery.
The results showed that (Z)-unsaturated phospholipid is a good substrate for sPLA2-IIA. The computational results are in good agreement with previously reported experimental data on the ability of sPLA2-IIA to hydrolyze liposomes made from the different phospholipids, and the results provide new insights into the necessary active-site solvation of the Michaelis-Menten complex and can pave the road for rational design in engineering applications.
Language: | English |
---|---|
Publisher: | American Chemical Society |
Year: | 2020 |
Pages: | 1881-1891 |
ISSN: | 15205207 and 15206106 |
Types: | Journal article |
DOI: | 10.1021/acs.jpcb.9b10837 |
ORCIDs: | 0000-0001-8648-3266 , 0000-0003-1411-9080 and Peters, Günther H.J. |