Past Results


Parmeggiani F et al. (2019) ACS Catalysis 9, 3482–3486.

In this collaborative project with the group of Nicholas Turner (U. Manchester), we used rational design to engineer the first reported aminotransferase displaying native-like catalytic activity towards D-tryptophan (kcat/KM = 700 M-1 s-1). This engineered variant enabled us to develop a one-pot biocatalytic process that combines asymmetric synthesis of substituted L-tryptophans from indoles by tryptophan synthase (TrpS), with a stereoinversion cascade based on L-amino acid deaminase (LAAD) and our engineered aminotransferase (DAAT). We show that this biocatalytic process can be used for the synthesis of 12 D-tryptophan derivatives containing electron-donating or withdrawing substituents at all benzene-ring positions on the indole group, with high conversion rate (84% to >99%) and enantiomeric excess (91% to >99%) starting from commercially-available materials. We also demonstrate that our process is applicable to preparative-scale synthesis of all 12 D-tryptophans (isolated yields of 63% to 79%), many of which are highly-valuable building blocks of pharmaceuticals and natural products.


Davey et al. (2017) Nature Chemical Biology 13, 1280-1285.

This manuscript presents the first demonstration of the rational design of proteins that can spontaneously exchange between two predefined conformational states in the absence of an external stimulus, and on a timescale relevant to function. To achieve this result, we developed a broadly-applicable computational method to engineer protein dynamics that we term meta-multistate design (meta-MSD). We used meta-MSD to design spontaneous exchange between two novel conformations introduced into the global fold of protein G domain β1 (Gβ1). The designed proteins, named DANCERs, for Dynamic And Native Conformational ExchangeRs, are stably folded and exchange between predicted conformational states on the millisecond timescale. Our new method for design of conformational exchange paves the way to the design of proteins with a more versatile range of functions than was previously possible, such as those that must adopt more than one conformational state (e.g., enzymes, molecular rotors, biosensors).


Pandelieva AT et al. (2016) ACS Chemical Biology 11, 508-517.

2016/09/01. We recently used rational design to increase the quantum yield and brightness of red fluorescent proteins (RFPs) by rigidifying their chromophore via the creation of a triple-decker motif of aromatic rings (see figure below). The best mutant identified displayed an over three-fold improvement relative to the parent RFP and was isolated following the screening of only 48 mutants, a library size that is several orders of magnitude smaller than those previously used to achieve equivalent gains in quantum yield in other RFPs.