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Abstract DNA barcoding based on mitochondrial (mt) nucleotide sequences is an enigma. Neutral models of mt evolution predict DNA barcoding cannot work for recently diverged taxa, and yet, mt DNA barcoding accurately delimits species for many bilaterian animals. Meanwhile, mt DNA barcoding often fails for plants and fungi. I propose that because mt gene products must cofunction with nuclear gene products, the evolution of mt genomes is best understood with full consideration of the two environments that impose selective pressure on mt genes: the external environment and the internal genomic environment. Moreover, it is critical to fully consider the potential for adaptive evolution of not just protein products of mt genes but also of mt transfer RNAs and mt ribosomal RNAs. The tight linkage of genes on mt genomes that do not engage in recombination could facilitate selective sweeps whenever there is positive selection on any element in the mt genome, leading to the purging of mt genetic diversity within a population and to the rapid fixation of novel mt DNA sequences. Accordingly, the most important factor determining whether or not mt DNA sequences diagnose species boundaries may be the extent to which the mt chromosomes engage in recombination.
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Computational generation of an annotated gigalibrary of synthesizable, composite peptidic macrocycles
Significance We describe computations to anticipate products of multistep reaction sequences. The work is based on experimental methods developed earlier to amalgamate synthetic scaffolding reagents with small linear peptides. Hybrid products retain molecular recognition elements in the peptide, but display that functionality as part of amphipathic macrocycles having defined conformations and improved pharmacological properties. The hypothetical scope of the chemistry is large and far outpaces the experimental format. To explore the structure space more extensively, we devised algorithms to predict outcomes of more than 2 billion processing sequences. Software was also developed to generate accurate three-dimensional structures for each product. The resultant virtual library is a resource that can be deployed broadly in search of novel ligands for protein receptors.
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- Award ID(s):
- 1764328
- PAR ID:
- 10193077
- Publisher / Repository:
- Proceedings of the National Academy of Sciences
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 117
- Issue:
- 40
- ISSN:
- 0027-8424
- Format(s):
- Medium: X Size: p. 24679-24690
- Size(s):
- p. 24679-24690
- Sponsoring Org:
- National Science Foundation
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