Protein Structure from Experimental Evolution
| Autor: | Debora S. Marks, Nicholas P. Gauthier, Richard R. Stein, Sachdev S. Sidhu, Michael A Stiffler, Kelly P Brock, Joan Teyra, Frank J. Poelwijk, Adam J. Riesselman, Chris Sander |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Experimental evolution Sequence Histology Protein family Computer science Protein Conformation Principle of maximum entropy Mutagenesis (molecular biology technique) Proteins Cell Biology Computational biology Pathology and Forensic Medicine Evolution Molecular 03 medical and health sciences 0302 clinical medicine Protein structure Humans Protein folding 030217 neurology & neurosurgery Selection (genetic algorithm) 030304 developmental biology |
| Zdroj: | Cell systems. 10(1) |
| ISSN: | 2405-4720 |
| Popis: | Summary Natural evolution encodes rich information about the structure and function of biomolecules in the genetic record. Previously, statistical analysis of co-variation patterns in natural protein families has enabled the accurate computation of 3D structures. Here, we explored generating similar information by experimental evolution, starting from a single gene and performing multiple cycles of in vitro mutagenesis and functional selection in Escherichia coli. We evolved two antibiotic resistance proteins, β-lactamase PSE1 and acetyltransferase AAC6, and obtained hundreds of thousands of diverse functional sequences. Using evolutionary coupling analysis, we inferred residue interaction constraints that were in agreement with contacts in known 3D structures, confirming genetic encoding of structural constraints in the selected sequences. Computational protein folding with interaction constraints then yielded 3D structures with the same fold as natural relatives. This work lays the foundation for a new experimental method (3Dseq) for protein structure determination, combining evolution experiments with inference of residue interactions from sequence information. A record of this paper’s Transparent Peer Review process is included in the Supplemental Information . |
| Databáze: | OpenAIRE |
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