Molecular dynamics study of secretory phospholipase A2 of Russell's viper and bovine pancreatic sources

A comparative molecular dynamics simulation of free and inhibitor-bound form of secretory phospholipase A(2) (sPLA(2)) of Russell's viper discloses the sort of restrictions in active site for inhibitor binding and implies suitable sites for further design of inhibitors based on active site scaffold. This enzyme belongs to group II PLA(2)s and dimerize asymmetrically with difference in orientation of W31 at the gateway of the active site of both the subunits. Hence, the active site of subunit A is open and that of subunit B is inaccessible to monodispersed inhibitors. PLA(2) enzymes are active at solvent-lipid interface and their action could be inhibited at the solvent environment before it reacts with aggregated substrates. Some sPLA(2)s, especially of different venom sources, undergo aggregation in a concentration-dependent manner, associate symmetrically into dimeric or trimeric form, and attain functional monomeric form during their interaction with the aggregated substrate. All sPLA(2)s exhibit catalysis with similar mechanism and show considerable differences in its way of inhibition. This necessitates conformational analysis on asymmetric dimer viper PLA(2) and its comparison with bovine pancreatic sPLA(2) (BPsPLA(2)) which belongs to group IB. BPsPLA(2) exists in monomeric form and does not have W31 at the gateway of hydrophobic pocket. In general, both monomeric and dimeric forms possess conserved active site with six subsites including the residues H48 and D49, and calcium-binding and surface loops. In the PLA(2) inhibitor complexes, the presence of calcium in monomer and W31 in dimer form is the unique feature and it makes the difference only in inhibitory mechanism without altering the catalytic mechanism. With this context, molecular dynamics simulation is performed for monomer and dimer form of sPLA(2)s in both native and complex forms. Comparison of trajectories with respect to fluctuation and deviation discloses the dynamics of surface and calcium-binding loops as well as the difference in dynamics of active site residues of group IB and II sPLA(2). Further, principal component and conformational cluster analyses are performed to substantiate the results.