DeGrado, W.F.; Korendovych, I.V.

Curr. Opin. Struct. Biol. 2014, 27, 113-121, 10.1016/j.sbi.2014.06.006

The de novo design of catalysts that mimic the affinity and specificity of natural enzymes remains one of the Holy Grails of chemistry. Despite decades of concerted effort we are still unable to design catalysts as efficient as enzymes. Here we critically evaluate approaches to (re)design of novel catalytic function in proteins using two test cases: Kemp elimination and ester hydrolysis. We show that the degree of success thus far has been modest when the rate enhancements seen for the designed proteins are compared with the rate enhancements by small molecule catalysts in solvents with properties similar to the active site. Nevertheless, there are reasons for optimism: the design methods are ever improving and the resulting catalyst can be efficiently improved using directed evolution.

Korendovych, I.V.

ACS Catal. 2019, 9, 9265-9275, 10.1021/acscatal.9b02509

The field of protein design has grown enormously in the past few decades. In this review, we discuss the minimalist approach to the design of artificial enzymes, in which protein sequences are created with the minimum number of elements for folding and function. This method relies on identifying starting points in catalytically inert scaffolds for active site installation. The progress of the field from the original helical assemblies of the 1980s to the more complex structures of the present day is discussed, highlighting the variety of catalytic reactions which have been achieved using these methods. We outline the strengths and weaknesses of the minimalist approaches, describe representative design cases, and put it in the general context of the de novo design of proteins.

Korendovych, I.V.

Angew. Chem. Int. Ed. 2020, 59, 8108-8112, 10.1002/anie.201916712

The self-assembly of short peptides gives rise to versatile nanoassemblies capable of promoting efficient catalysis. We have semi-rationally designed a series of seven-residue peptides that form hemin-binding catalytic amyloids to facilitate enantioselective cyclopropanation with efficiencies that rival those of engineered hemin proteins. These results demonstrate that: 1) Catalytic amyloids can bind complex metallocofactors to promote practically important multisubstrate transformations. 2) Even essentially flat surfaces of amyloid assemblies can impart a substantial degree of enantioselectivity without the need for extensive optimization. 3) The ease of peptide preparation allows for straightforward incorporation of unnatural amino acids and the preparation of peptides made from d-amino acids with complete reversal of enantioselectivity.