Trapping a transition state in a computationally designed protein bottle

Aaron D. Pearson, Jeremy H. Mills, Yifan Song, Fariborz Nasertorabi, Gye Won Han, David Baker, Raymond C. Stevens, Peter G. Schultz

Research output: Contribution to journalArticle

26 Scopus citations


The fleeting lifetimes of the transition states (TSs) of chemical reactions make determination of their three-dimensional structures by diffraction methods a challenge. Here, we used packing interactions within the core of a protein to stabilize the planar TS conformation for rotation around the central carbon-carbon bond of biphenyl so that it could be directly observed by x-ray crystallography. The computational protein design software Rosetta was used to design a pocket within threonyl-transfer RNA synthetase from the thermophile Pyrococcus abyssi that forms complementary van der Waals interactions with a planar biphenyl.This latter moiety was introduced biosynthetically as the side chain of the noncanonical amino acid p-biphenylalanine. Through iterative rounds of computational design and structural analysis, we identified a protein in which the side chain of p-biphenylalanine is trapped in the energetically disfavored, coplanar conformation of the TS of the bond rotation reaction.

Original languageEnglish (US)
Pages (from-to)863-867
Number of pages5
Issue number6224
StatePublished - Feb 20 2015
Externally publishedYes


ASJC Scopus subject areas

  • General

Cite this

Pearson, A. D., Mills, J. H., Song, Y., Nasertorabi, F., Han, G. W., Baker, D., Stevens, R. C., & Schultz, P. G. (2015). Trapping a transition state in a computationally designed protein bottle. Science, 347(6224), 863-867.