A quantum mechanical/molecular mechanical model of inhibition of the enzyme phospholipase A2

Abstract

The mechanism of catalysis within the enzyme phospholipase A₂ has been investigated by a combination of ab initio molecular orbital, molecular mechanics and free energy perturbation calculations. The computational model has been used to quantify the energetics of binding and hydrolysis of a carbamate phospholipid, and to rationalise the differences in reactivity of carbamate, ester and amide phospholipids. The binding of fluorinated ketone analogues is also discussed. A number of aspects of the calculations are critically examined and the method is shown to be a powerful tool in the investigation of catalytic reaction paths in macromolecular systems.