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Directed Chemical Evolution with an Outsized Genetic Code

Krusemark, Casey J ; Tilmans, Nicolas P ; Brown, Patrick O ; Harbury, Pehr B Isalan, Mark

PloS one, 2016-08, Vol.11 (8), p.e0154765-e0154765 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Directed Chemical Evolution with an Outsized Genetic Code
Autor: Krusemark, Casey J ; Tilmans, Nicolas P ; Brown, Patrick O ; Harbury, Pehr B
Isalan, Mark
Assuntos: Alphabets ; Amino acids ; Analysis ; Biochemistry ; Biology and life sciences ; Chemical evolution ; Chemical evolution (Biology) ; Chemical evolution (Origin of life) ; Chemical synthesis ; Combinatorial analysis ; Combinatorial chemistry ; Deoxyribonucleic acid ; Directed evolution ; DNA ; DNA - genetics ; DNA - metabolism ; Engineering ; Engineering and Technology ; Evolution ; Evolution, Chemical ; Feasibility studies ; Fitness ; Gene amplification ; Gene Library ; Genetic Code ; Genetics ; Immunoglobulins ; Kinases ; Kinetics ; Macromolecules ; Models, Theoretical ; Mutation ; Organic chemistry ; Peptide Library ; Peptides ; Peptides - chemistry ; Peptides - genetics ; Peptides - metabolism ; Population ; Protein Engineering ; Proteins ; Reproductive fitness ; Research and Analysis Methods ; Small Molecule Libraries - chemistry ; Substrate Specificity ; Tagging
É parte de: PloS one, 2016-08, Vol.11 (8), p.e0154765-e0154765
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Conceived and designed the experiments: CJK POB PBH. Performed the experiments: CJK NPT. Analyzed the data: CJK POB PBH. Wrote the paper: CJK PBH.
Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: (1) Pehr Harbury is a founder and scientific advisory board member of DiCE LLC, a biotech company which is commercializing DNA programmed combinatorial chemistry; (2) Pat Brown is a founder and chief scientific officer of Impossible Foods, a biotech company which has licensed a DNA programmed combinatorial chemistry patent from Stanford University. Pehr Harbury's relationship with DiCE Molecules LLC and Pat Brown's relationship with Impossible Foods does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.
Current address: Impossible Foods, Redwood City, California, United States of America
Descrição: The first demonstration that macromolecules could be evolved in a test tube was reported twenty-five years ago. That breakthrough meant that billions of years of chance discovery and refinement could be compressed into a few weeks, and provided a powerful tool that now dominates all aspects of protein engineering. A challenge has been to extend this scientific advance into synthetic chemical space: to enable the directed evolution of abiotic molecules. The problem has been tackled in many ways. These include expanding the natural genetic code to include unnatural amino acids, engineering polyketide and polypeptide synthases to produce novel products, and tagging combinatorial chemistry libraries with DNA. Importantly, there is still no small-molecule analog of directed protein evolution, i.e. a substantiated approach for optimizing complex (≥ 10^9 diversity) populations of synthetic small molecules over successive generations. We present a key advance towards this goal: a tool for genetically-programmed synthesis of small-molecule libraries from large chemical alphabets. The approach accommodates alphabets that are one to two orders of magnitude larger than any in Nature, and facilitates evolution within the chemical spaces they create. This is critical for small molecules, which are built up from numerous and highly varied chemical fragments. We report a proof-of-concept chemical evolution experiment utilizing an outsized genetic code, and demonstrate that fitness traits can be passed from an initial small-molecule population through to the great-grandchildren of that population. The results establish the practical feasibility of engineering synthetic small molecules through accelerated evolution.
Editor: United States: Public Library of Science
Idioma: Inglês

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Directed Chemical Evolution with an Outsized Genetic Code

Krusemark, Casey J ; Tilmans, Nicolas P ; Brown, Patrick O ; Harbury, Pehr B Isalan, Mark

United States: Public Library of Science

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