Are natural proteins special? Can we do that?

Hecht, Michael H.; Zarzhitsky, Shlomo; Karas, Christina; Chari, Sarangan L

doi:10.1016/j.sbi.2017.11.009

Cited by 16 publications

(17 citation statements)

References 79 publications

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“…A “conservative” solution to create novel proteins would be to fully exploit the potential of the 20 canonical amino acids encoded by the SGC. Indeed, concepts for systematically designing entire libraries of “non-natural proteins” (based on the canonical amino acid repertoire) that can be employed in vivo to replace natural proteins have been presented, and proof of their practicability has been provided [51–53]. A second possibility is to expand or alter the genetic code.…”

Section: Novel Approaches To Bypassing Roadblocks Caused By Fmasmentioning

confidence: 99%

“…Of the compatible fraction, only a very tiny part has been exposed to evolutionary pressures on Earth, leaving a vast number of non-natural proteins capable of replacing existing natural proteins or mediating entirely novel functions. This concept is not only plausible; it has already been shown to be practicable [51]. Libraries of non-natural proteins with the potential to sustain the growth of living cells can be constructed in a systematic and knowledge-based manner, and non-natural proteins that perform specific functions have been identified by phenotypically complementing mutations in natural proteins [51].…”

Section: Exploiting Non-natural Sequence Variations To Enhance Psii Fmentioning

confidence: 99%

“…This concept is not only plausible; it has already been shown to be practicable [51]. Libraries of non-natural proteins with the potential to sustain the growth of living cells can be constructed in a systematic and knowledge-based manner, and non-natural proteins that perform specific functions have been identified by phenotypically complementing mutations in natural proteins [51]. This approach has resulted in the identification of non-natural proteins that rescued deletion mutants lacking natural proteins with various specific activities, including phosphoserine phosphatase, citrate synthase, threonine deaminase, and enterobactin esterase [68].…”

Section: Exploiting Non-natural Sequence Variations To Enhance Psii Fmentioning

confidence: 99%

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Thawing out frozen metabolic accidents

Leister

2019

BMC Biol

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Photosynthesis and nitrogen fixation became evolutionarily immutable as “frozen metabolic accidents” because multiple interactions between the proteins and protein complexes involved led to their co-evolution in modules. This has impeded their adaptation to an oxidizing atmosphere, and reconfiguration now requires modification or replacement of whole modules, using either natural modules from exotic species or non-natural proteins with similar interaction potential. Ultimately, the relevant complexes might be reconstructed (almost) from scratch, starting either from appropriate precursor processes or by designing alternative pathways. These approaches will require advances in synthetic biology, laboratory evolution, and a better understanding of module functions.

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Section: Novel Approaches To Bypassing Roadblocks Caused By Fmasmentioning

confidence: 99%

Section: Exploiting Non-natural Sequence Variations To Enhance Psii Fmentioning

confidence: 99%

Section: Exploiting Non-natural Sequence Variations To Enhance Psii Fmentioning

confidence: 99%

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Thawing out frozen metabolic accidents

Leister

2019

BMC Biol

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“…binding, scaffolding, and catalysis). While the set of extant protein sequences is large (>10 6 ), it is only a miniscule fraction of all possible protein sequences (Hecht et al, 2018). Indeed, early efforts in protein design and engineering established that natural protein sequences could be modified to possess properties useful outside biological systems and that entirely de novo proteins could be created with structures and functions not observed in nature (Dahiyat and Mayo, 1997; Hecht et al, 1990; Kamtekar et al, 1993; Kuhlman et al, 2003; Moore and Arnold, 1996; Regan and Degrado, 1988).…”

Section: Introductionmentioning

confidence: 99%

Mutation Maker, An Open Source Oligo Design Platform for Protein Engineering

Hiraga

Mejzlík²,

Marcisin³

et al. 2020

Preprint

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Founded on principles of natural selection, directed evolution techniques harness high-throughput gene diversification methodologies to generate proteins with optimized properties for applications in research, therapeutic and industrial processes. However, design of gene libraries is typically hampered by scale and complexity, necessitating development of advanced automation and optimization tools that can improve efficiency and accuracy. At present, automated library design tools are obsolete, functionally limited or not freely available for commercial use. To address these issues, we developed Mutation Maker, an open source mutagenic oligo design software for large-scale protein engineering experiments. Mutation Maker is not only specifically tailored to multi-site random and directed mutagenesis protocols, but also pioneers bespoke mutagenic oligo design for de novo gene synthesis workflows. Enabled by a novel bundle of orchestrated heuristics, optimization, constraint-satisfaction and backtracking algorithms, Mutation Maker offers a versatile toolbox for gene diversification design at industrial scale. Supported by in-silico simulations and compelling experimental validation data, Mutation Maker oligos produce diverse gene libraries at high success rates irrespective of genes or vectors used. Finally, Mutation Maker was created as an extensible platform on the notion that directed evolution techniques will continue to evolve and revolutionize current and future-oriented applications.

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“…11 Using the proteins they have designed, the Hecht Lab seeks to show that natural proteins are not "special" and that their functions can be replicated with synthetic enzymes. 12,13 While this work and the work of similar research groups may someday revolutionize the way we approach synthesis, it is not yet possible to simply design an enzyme to complete any synthesis step. For the time being, chemists have been successful in developing protocols to link small molecules together with highly specified orientations and orders.…”

Section: Edgmentioning

confidence: 99%

A Computational Investigation of the Initiation Mechanisms of Thiol-Vinyl Sulfone Reactions

Wollowitz¹

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Are natural proteins special? Can we do that?

Cited by 16 publications

References 79 publications

Thawing out frozen metabolic accidents

Thawing out frozen metabolic accidents

Mutation Maker, An Open Source Oligo Design Platform for Protein Engineering

A Computational Investigation of the Initiation Mechanisms of Thiol-Vinyl Sulfone Reactions

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