Minimal-alphabet proteins by evolution, engineering, and design.

Authors

Filip Buchel, Valerio G Giacobelli, Klára Hlouchová

Published in

Trends in biochemical sciences. Aug 28, 2026. Epub Aug 28, 2026.

Abstract

Research on the structural and functional potential of minimal amino acid alphabets is shifting from reductive 'pruning' of extant proteins to bottom-up exploration of combinatorial sequence space. This review highlights the experimental and computational toolkits driving this transition. We discuss how solid-phase peptide synthesis, genetically encoded libraries, and high-throughput selection and screening enable systematic exploration of vast, noncanonical landscapes largely inaccessible to traditional engineering. Integrating these approaches with generative machine learning and de novo protein design allows researchers to move beyond observing what evolution produced toward exploring what chemistry permits. Together, these advances are redirecting the field from simplifying extant proteins to uncovering the physicochemical principles governing protein foldability, while expanding the design space beyond the constraints imposed by biological evolution.

PMID:
42665456
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.

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