Secretory phospholipases A(2) (sPLA(2)s) 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 sPLA(2)-IIA pass by the aromatic residues Phe(5) and Tyr(51) and enter the active site through an active-site cleft. The relative amount of water available for the enzymatic reaction of the different phospholipid-sPLA(2) 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 sPLA(2)-IIA. The computational results are in good agreement with previously reported experimental data on the ability of sPLA(2)-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.