A Zinc-containing protein (1) was found to catalyze specific bimolecular Diels-Alder reactions with high catalytic efficiency and enantioselectivity. Currently we aim at modifying the architecture of 1 to reverse its catalytic enantioselectivity with the assist of quantum mechanical calculation and molecular dynamic simulation techniques. Our novel approach comprises construction of the antipode of the chiral binding pocket in the original protein (1) by C2 symmetrical manipulation of the tetra-helical tertiary structure of 1 via computationally-guided mutagenesis. The resulting mutant (2) mimicries the antipode of the tertiary structure of 1 and provides a binding pocket for the transition state which leads to the opposite enantiomer produced by 1. The key designing process includes scaffold-shift, stability-reinforcement, inside-out fitting of the substrate, and final elaboration of residues. This approach would provide a general protocol for rational structural-modification of functional proteins.

Change the enantioselectivity of enzymes: Rational structural-modification of functional proteins catalyzing Diels-Alder reactions with the reversed enantioselectivity

2019 Fall National Meeting

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