Computer-aided design of artificial enzymes: cyclic urea mimetics of alpha-chymotrypsin

We use molecular mechanics to calculate the conformational properties of a cyclic urea mimetic of alpha-chymotrypsin proposed, but not yet synthesized, by Cram and co-workers. We find that, in order to bring the structural elements of the catalytic triad into a spatial orientation suitable for proton transfer, the proposed enzyme mimetic must adopt a highly strained conformation. We redesign that part of the molecular architecture holding the catalytic triad in position and suggest two alternative enzyme mimetics. Of these, we find that the mimetic containing a fused ring structure positions the components of the catalytic triad at reasonable distances for proton transfer. We study the effect of these structural alterations on the recognition pattern presented by the enzyme mimetic to the substrate, as illustrated by the molecular electrostatic potential of the artificial enzyme.