Stereoelectronic and Steric Effects in the Collagen Triple Helix: Toward a Code for Strand Association
- 19 October 2005
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 127 (45), 15923-15932
- https://doi.org/10.1021/ja054674r
Abstract
Collagen is the most abundant protein in animals. The protein consists of a helix of three strands, each with sequence X−Y−Gly. Natural collagen is most stable when X is (2S)-proline (Pro) and Y is (2S,4R)-4-hydroxyproline (4R-Hyp). We had shown previously that triple helices in which X is (2S,4S)-4-fluoroproline (4S-Flp) or Y is (2S,4R)-4-fluoroproline (4R-Flp) display hyperstability. This hyperstability arises from stereoelectronic effects that preorganize the main-chain dihedral angles in the conformation found in the triple helix. Here, we report the synthesis of strands containing both 4S-Flp in the X-position and 4R-Flp in the Y-position. We find that these strands do not form a stable triple helix, presumably because of an unfavorable steric interaction between fluoro groups on adjacent strands. Density functional theory calculations indicate that (2S,3S)-3-fluoroproline (3S-Flp), like 4S-Flp, should preorganize the main chain properly for triple-helix formation but without a steric conflict. Synthetic strands containing 3S-Flp in the X-position and 4R-Flp in the Y-position do form a triple helix. This helix is, however, less stable than one with Pro in the X-position, presumably because of an unfavorable inductive effect that diminishes the strength of the interstrand 3S-FlpCO···HNGly hydrogen bond. Thus, other forces can counter the benefits derived from the proper preorganization. Although (Pro−Pro−Gly)7 and (4S-Flp−4R-Flp−Gly)7 do not form stable homotrimeric helices, mixtures of these two peptides form stable heterotrimeric helices containing one (Pro−Pro−Gly)7 strand and two (4S-Flp−4R-Flp−Gly)7 strands. This stoichiometry can be understood by considering the cross sections of the two possible heterotrimeric helices. This unexpected finding portends the development of a “code” for the self-assembly of determinate triple helices from two or three strands.Keywords
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