2005 Emil Thomas Kaiser Award - PubMed (original) (raw)

2005 Emil Thomas Kaiser Award

Ronald T Raines. Protein Sci. 2006 May.

Abstract

Collagen is the most abundant protein in animals. The conformational stability of the collagen triple helix is enhanced by the hydroxyl group of its prevalent (2S,4R)-4-hydroxyproline residues. For 25 years, the prevailing paradigm had been that this enhanced stability is due to hydrogen bonds mediated by bridging water molecules. We tested this hypothesis with synthetic collagen triple helices containing 4-fluoroproline residues. The results have unveiled a wealth of stereoelectronic effects that contribute markedly to the stability of collagen, as well as other proteins. This new understanding is leading to synthetic collagens for a variety of applications in biotechnology and biomedicine.

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Figures

Figure 1.

Figure 1.

Correlation of ring pucker with collagen triple helix stability (Inouye et al. 1976; Bretscher et al. 2001; DeRider et al. 2002). In a crystalline triple helix, proline residues have ϕ = –73°, ψ = 164° in the Xaa position, and ϕ = –60°, ψ = 150° in the Yaa position (Bella et al. 1994).

Figure 2.

Figure 2.

Ring conformations of 4-substituted proline residues. The Cγ-endo conformation is favored strongly when R1 = H and R2 = F (as in flp). The Cγ-exo conformation is favored strongly when R1 = OH (Hyp) or F (Flp) and R2 = H. The Cγ-exo:Cγ-endo ratio is ∼1:2 when R1 = R2 = H (Pro) (DeRider et al. 2002).

Figure 3.

Figure 3.

Natural bond orbitals depicting the n → π* interaction between O′i–1 and C′ in the trans peptide bond isomer of AcProOMe having Cγ-exo ring pucker (DeRider et al. 2002; Hinderaker and Raines 2003).

Figure 4.

Figure 4.

Structures of Ac–methano-Pro–OMe and Ac–methano-flp–OMe, which have amide bonds with indistinguishable trans:cis ratios (Jenkins et al. 2004).

Figure 5.

Figure 5.

Trans:cis ratio of FmProOMe. The free energy of the n → π* interaction was estimated from experimental and theoretical data (DeRider et al. 2002; Hinderaker and Raines 2003).

Figure 6.

Figure 6.

Basis of a code for triple helix formation. (A) Prevalent ring conformations of Pro, flp, and Flp (DeRider et al. 2002). (B) Depiction of the favorable (Flp···Pro) and (Pro···flp) and unfavorable (flp···Flp) steric interactions within cross-sections of a triple helix (Hodges and Raines 2005).

Figure 7.

Figure 7.

Interactions that stabilize the common elements of secondary structure as embedded within the major resonance forms of the peptide bond.

Figure 8.

Figure 8.

Structure of a synthetic collagen fragment that self-assembles into fibrils of 1-nm width and nearly 1-μm length (Kotch and Raines 2006).

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References

    1. Bella J., Eaton M., Brodsky B., Berman H.M. 1994. Crystal and molecular structure of a collagen-like peptide at 1.9 Å resolution Science 266: 75–81. - PubMed
    1. Brand L. and Gohlke J.R. 1972. Fluorescence probes for structure Annu. Rev. Biochem. 41: 843–868. - PubMed
    1. Bretscher L.E., Jenkins C.L., Taylor K.M., DeRider M.L., Raines R.T. 2001. Conformational stability of collagen relies on a stereoelectronic effect J. Am. Chem. Soc. 123: 777–778. - PubMed
    1. Briggs C.R.S., O'Hagan D., Howard J.A.K., Yufit D.S. 2003. The C–F bond as a tool in the conformational control of amides J. Fluor. Chem. 119: 9–13.
    1. Bürgi H.B., Dunitz J.D., Shefter E. 1973. Geometrical reaction coordinates. II. Nucleophilic addition to a carbonyl group J. Am. Chem. Soc. 95: 5065–5067.

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