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Published online before print November 22, 2006, 10.1110/ps.062557707
Protein Science (2007), 16:14-19. Published by Cold Spring Harbor Laboratory Press. Copyright © 2007 The Protein Society
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Solution structure of a small protein containing a fluorinated side chain in the core

Gabriel Cornilescu1, Erik B. Hadley2, Matthew G. Woll2, John L. Markley1, Samuel H. Gellman2, and Claudia C. Cornilescu1

1 NMRFAM, Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, USA
2 Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA

(RECEIVED September 13, 2006; FINAL REVISION October 6, 2006; ACCEPTED October 10, 2006)

We report the first high-resolution structure for a protein containing a fluorinated side chain. Recently we carried out a systematic evaluation of phenylalanine to pentafluorophenylalanine (Phe -> F5-Phe) mutants for the 35-residue chicken villin headpiece subdomain (c-VHP), the hydrophobic core of which features a cluster of three Phe side chains (residues 6, 10, and 17). Phe -> F5-Phe mutations are interesting because aryl–perfluoroaryl interactions of optimal geometry are intrinsically more favorable than either aryl–aryl or perfluoroaryl–perfluoroaryl interactions, and because perfluoroaryl units are more hydrophobic than are analogous aryl units. Only one mutation, Phe10 -> F5-Phe, was found to provide enhanced tertiary structural stability relative to the native core (by ~1 kcal/mol, according to guanidinium chloride denaturation studies). The NMR structure of this mutant, described here, reveals very little variation in backbone conformation or side chain packing relative to the wild type. Thus, although Phe -> F5-Phe mutations offer the possibility of greater tertiary structural stability from side chain–side chain attraction and/or side chain desolvation, the constraints associated with the native c-VHP fold apparently prevent the modified polypeptide from taking advantage of this possibility. Our findings are important because they complement several studies that have shown that fluorination of saturated side chain carbon atoms can provide enhanced conformational stability.

Keywords: pentafluorophenylalanine; backbone thioester exchange; villin headpiece; NMR; 1H/19F and 19F/1H heteronuclear NOE


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