We used the Nb-catalyzed epoxidation reaction of ethylene to study a series of important features of reactivity simulations of metal-doped amorphous materials. The simulations are necessary to provide mechanistic insights in the catalytic activity of materials, which may lead to rational design of more selective or more active heterogeneous catalysts. However, there are many open questions about how to perform reliable simulations, and we addressed several issues in this work as summarized below.