Front Cover: Design of a Full‐Consensus Glutamate Decarboxylase and Its Application to GABA Biosynthesis (ChemBioChem 8/2022)

Efficient Exploration of Sequence Space by Sequence-Guided Protein Engineering and Design

“…Thus, protein variants with improved thermostability can be obtained through amino acid substitutions that restore the consensus amino acid at each position; these substitutions can be introduced individually into a single protein, incorporated into libraries for directed evolution, or combined to create a full-length consensus sequence . Although there have been numerous recent examples in which consensus design has been used successfully to increase protein thermostability, − the method suffers from sensitivity to phylogenetic bias caused by inclusion of closely related sequences in the analysis and does not account for amino acid covariation at different positions in the multiple-sequence alignment . Recent work has continued to refine, generalize, and systematically validate the consensus design methodology; − for example, using a standardized workflow with very large sequence data sets (1355–14474 sequences), Sternke et al applied consensus design to six structurally and functionally diverse protein families and achieved increased thermostability compared to that of naturally occurring homologues (including those from thermophilic organisms) in four of six cases .…”