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Stereoelectronic effects on polyproline conformation

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

(RECEIVED August 15, 2005; FINAL REVISION October 4, 2005; ACCEPTED October 11, 2005)

The polyproline type II (PPII) helix is a prevalent conformation in both folded and unfolded proteins, and is known to play important roles in a wide variety of biological processes. Polyproline itself can also form a type I (PPI) helix, which has a disparate conformation. Here, we use derivatives of polyproline, (Pro)₁₀, (Hyp)₁₀, (Flp)₁₀, and (flp)₁₀, where Hyp is (2S,4R)-4-hydroxyproline, Flp is (2S,4R)-4-fluoroproline, and flp is (2S,4S)-4-fluoroproline, to probe for a stereoelectronic effect on the conformation of polyproline. Circular dichroism spectral analyses show that 4R electron-with-drawing substituents stabilize a PPII helix relative to a PPI helix, even in a solvent that favors the PPI conformation, such as n-propanol. The stereochemistry at C4 ordains the relative stability of PPI and PPII helices, as (flp)₁₀ forms a mixture of PPI and PPII helices in water and a PPI helix in n-propanol. The conformational preferences of (Pro)₁₀ are intermediate between those of (Hyp)₁₀/(Flp)₁₀ and (flp)₁₀. Interestingly, PPI helices of (flp)₁₀ exhibit cold denaturation in n-propanol with a value of T_s near 70°C. Together, these data show that stereoelectronic effects can have a substantial impact on polyproline conformation and provide a rational means to stabilize a PPI or PPII helix.

Keywords: cold denaturation; collagen; fluoroproline; helix; hydroxyproline; polyproline; stereoelectronic effect

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051779806.

Reprint requests to: Ronald T. Raines, Department of Biochemistry, University of Wisconsin—Madison, 433 Babcock Drive, Madison, WI 53706-1544, USA; e-mail: raines{at}biochem.wisc.edu; fax: (608) 262-3453.

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