Tuning phenylalanine fluorination to assess aromatic contributions to protein function and stability in cells

Grace D. Galles, Daniel T. Infield, Colin J. Clark, Marcus L. Hemshorn, Shivani Manikandan, Frederico Fazan, Ali Rasouli, Emad Tajkhorshid, Jason D. Galpin, Richard B. Cooley, Ryan A. Mehl and Christopher A. Ahern ()
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Grace D. Galles: University of Iowa College of Medicine
Daniel T. Infield: University of Iowa College of Medicine
Colin J. Clark: University of Iowa College of Medicine
Marcus L. Hemshorn: Oregon State University
Shivani Manikandan: University of Iowa College of Medicine
Frederico Fazan: University of Iowa College of Medicine
Ali Rasouli: University of Illinois at Urbana-Champaign
Emad Tajkhorshid: University of Illinois at Urbana-Champaign
Jason D. Galpin: University of Iowa College of Medicine
Richard B. Cooley: Oregon State University
Ryan A. Mehl: Oregon State University
Christopher A. Ahern: University of Iowa College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract The aromatic side-chains of phenylalanine, tyrosine, and tryptophan interact with their environments via both hydrophobic and electrostatic interactions. Determining the extent to which these contribute to protein function and stability is not possible with conventional mutagenesis. Serial fluorination of a given aromatic is a validated method in vitro and in silico to specifically alter electrostatic characteristics, but this approach is restricted to a select few experimental systems. Here, we report a group of pyrrolysine-based aminoacyl-tRNA synthetase/tRNA pairs (tRNA/RS pairs) that enable the site-specific encoding of a varied spectrum of fluorinated phenylalanine amino acids in E. coli and mammalian (HEK 293T) cells. By allowing the cross-kingdom expression of proteins bearing these unnatural amino acids at biochemical scale, these tools may potentially enable the study of biological mechanisms which utilize aromatic interactions in structural and cellular contexts.

Date: 2023
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DOI: 10.1038/s41467-022-35761-w

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