Human secreted
phospholipase A2s have been shown to promote
inflammation in mammals by catalyzing the first step of the
arachidonic acid pathway by breaking down
phospholipids, producing
fatty acids, including
arachidonic acid. They bind to the membrane water interface to access their
phospholipid substrates from the membrane. Their binding modes on membrane surfaces are regulated by diverse factors, including membrane charge, fluidity, and heterogeneity. The influence of these factors on the binding modes of the
enzymes is not well understood. Here we have studied several human synovial
phospholipase A2 (hs-PLA2)/mixed bilayer systems through a combined coarse-grain and all-atom molecular dynamics simulation. It was found that hydrophobic residues Leu2, Val3, Ala18, Leu19, Phe23, Gly30, and Phe63 that form the edge of the entrance of the hydrophobic binding pocket in hs-PLA2 tend to penetrate into the hydrophobic area of
lipid bilayers, and more than half of the total
amino acid residues make contact with the
lipid headgroups. Each
enzyme molecule forms 19-38 hydrogen bonds with the bilayer to which it binds, most of which are with the
phosphate groups. Analysis of the root-mean-square deviation (rmsd) shows that residues Val30-Thr40, Tyr66-Gln80, and Lys107-Arg118 have relatively large rmsds during all-atom molecular dynamics simulations, in accordance with the observation of an enlarged entrance region of the hydrophobic binding pocket. The amino acid sequences forming the entrance of the binding pocket prefer to interact with
lipid molecules that are more fluid or negatively charged, and the opening of the binding pocket would be larger when the
lipid components are more fluid.