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Review
. 2015 Sep 15:582:68-79.
doi: 10.1016/j.abb.2015.03.013. Epub 2015 Mar 19.

Computational strategies for the design of new enzymatic functions

K Świderek  1 , I Tuñón  2 , V Moliner  3 , J Bertran  4
Affiliations
Review

Computational strategies for the design of new enzymatic functions

K Świderek et al. Arch Biochem Biophys. .

Abstract

In this contribution, recent developments in the design of biocatalysts are reviewed with particular emphasis in the de novo strategy. Studies based on three different reactions, Kemp elimination, Diels-Alder and Retro-Aldolase, are used to illustrate different success achieved during the last years. Finally, a section is devoted to the particular case of designed metalloenzymes. As a general conclusion, the interplay between new and more sophisticated engineering protocols and computational methods, based on molecular dynamics simulations with Quantum Mechanics/Molecular Mechanics potentials and fully flexible models, seems to constitute the bed rock for present and future successful design strategies.

Keywords: De novo design; Diels–Alder; Kemp elimination; Molecular dynamics; Protein design; QM/MM; Retro-Aldolase.

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Figures

Figure 1
Figure 1
Schematic representation of the de novo design of new enzymes
Figure 2
Figure 2
Schematic representation of an artificial metalloenzyme, where a metal ligand complex is posed in the cavity of an enzyme by means of different possible anchoring strategies.
Figure 3
Figure 3
Schematic representation of of proposed artificial metalloenzymes based on Cu(II) complexes grafted on the dimer interface of a protein.
Figure 4
Figure 4
Schematic representation of of proposed artificial metalloenzymes based on modular assembly of a copper complex of a non-chiral ligand to a DNA scaffold.
Figure 5
Figure 5
Crystal structure of the binuclear center of cytochrome ba3 oxidase (PDB code 1XME).
Figure 6
Figure 6
Schematic representation of artificial metalloenzymes based on the biotinavidin technology.
Scheme 1
Scheme 1
Representation of the base-catalyzed Kemp elimination
Scheme 2
Scheme 2
Representation of the Diels Alder cycloaddition reaction
Scheme 3
Scheme 3
Representation of the Retro-Aldol reaction mechanism
Scheme 4
Scheme 4
Representation of the Diels-Alder cycloadition between azachalcone and cyclopentadiene
See this image and copyright information in PMC

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