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Computational Analysis of a Prebiotic Amino Acid Synthesis with Reference to Extant Codon-Amino Acid Relationships.

ABSTRACT: Novel density functional theory calculations are presented regarding a mechanism for prebiotic amino acid synthesis from alpha-keto acids that was suggested to happen via catalysis by dinucleotide species. Our results were analysed with comparison to the original hypothesis (Copley et al., PNAS, 2005, 102, 4442-4447). It was shown that the keto acid-dinucleotide hypothesis for possible prebiotic amino acid synthesis was plausible based on an initial computational analysis, and details of the structures for the intermediates and transition states showed that there was wide scope for interactions between the keto acid and dinucleotide moieties that could affect the free energy profiles and lead to the required proto-metabolic selectivity.

SUBMITTER: Yaman T

PROVIDER: S-EPMC8707928 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Computational Analysis of a Prebiotic Amino Acid Synthesis with Reference to Extant Codon-Amino Acid Relationships.

Yaman Tolga T Harvey Jeremy N JN

Life (Basel, Switzerland) 20211204 12

Novel density functional theory calculations are presented regarding a mechanism for prebiotic amino acid synthesis from alpha-keto acids that was suggested to happen via catalysis by dinucleotide species. Our results were analysed with comparison to the original hypothesis (Copley et al., <i>PNAS</i>, <b>2005</b>, 102, 4442-4447). It was shown that the keto acid-dinucleotide hypothesis for possible prebiotic amino acid synthesis was plausible based on an initial computational analysis, and deta ...[more]

PMID: 34947874

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Project description:BackgroundGlobal residue-specific amino acid mutagenesis can provide important biological insight and generate proteins with altered properties, but at the risk of protein misfolding. Further, targeted libraries are usually restricted to a handful of amino acids because there is an exponential correlation between the number of residues randomized and the size of the resulting ensemble. Using GFP as the model protein, we present a strategy, termed protein evolution via amino acid and codon elimination, through which simplified, native-like polypeptides encoded by a reduced genetic code were obtained via screening of reduced-size ensembles.Methodology/principal findingsThe strategy involves combining a sequential mutagenesis scheme to reduce library size with structurally stabilizing mutations, chaperone complementation, and reduced temperature of gene expression. In six steps, we eliminated a common buried residue, Phe, from the green fluorescent protein (GFP), while retaining activity. A GFP variant containing 11 Phe residues was used as starting scaffold to generate 10 separate variants in which each Phe was replaced individually (in one construct two adjacent Phe residues were changed simultaneously), while retaining varying levels of activity. Combination of these substitutions to generate a Phe-free variant of GFP abolished fluorescence. Combinatorial re-introduction of five Phe residues, based on the activities of the respective single amino acid replacements, was sufficient to restore GFP activity. Successive rounds of mutagenesis generated active GFP variants containing, three, two, and zero Phe residues. These GFPs all displayed progenitor-like fluorescence spectra, temperature-sensitive folding, a reduced structural stability and, for the least stable variants, a reduced steady state abundance.Conclusions/significanceThe results provide strategies for the design of novel GFP reporters. The described approach offers a means to enable engineering of active proteins that lack certain amino acids, a key step towards expanding the functional repertoire of uniquely labeled proteins in synthetic biology.

Dataset Information

Computational Analysis of a Prebiotic Amino Acid Synthesis with Reference to Extant Codon-Amino Acid Relationships.

Publications

Computational Analysis of a Prebiotic Amino Acid Synthesis with Reference to Extant Codon-Amino Acid Relationships.

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