Water-Intake and Water-Molecule Paths to the Active Site of Secretory Phospholipase A2 Studied Using MD Simulations and the Tracking Tool AQUA-DUCT

• Published in: The journal of physical chemistry. B Vol. 124; no. 10; pp. 1881 - 1891
• Main Authors: Tjørnelund, Helena D, Madsen, Jesper J, Peters, Günther H. J
• Format: Journal Article
• Language: English
• Published: American Chemical Society 12-03-2020
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/acs.jpcb.9b10837

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.