Future strategies for sustainable energy production will undoubtedly require processes and materials that can efficiently convert renewable resources into fuels. Nature's enzymes can exquisitely integrate highly active catalytic centers within flexible environments that can adaptively guide reactants to products with very high activities and selectivities. They are limited, however, by their stability and ability to integrate into large scale production processes. The design of more robust heterogeneous catalytic materials that mimic the performance of enzymes, however, has been hindered by our limited understanding of how such transformations proceed. The tremendous advances in ab initio quantum mechanical methods, atomistic simulations, and high performance computing that have occurred over the past two decades, however, provide unprecedented ability to track molecular transformations and how they proceed at specific sites and within particular environments. This information together with the advances in in situ spectroscopic methods that follow such transformations can begin to enable the design of atomic surface ensembles and nanoscale reaction environments. This paper provides the author's perspective on how theory and simulation can be used to move from current one-dimensional design efforts based on catalytic descriptors to the design of two-dimensional surfaces, three-dimensional reaction environments, and proton-coupled electron transfer systems that mimic enzymes in the transformation of molecules.