Effect of 3-Hydroxyproline Residues on Collagen Stability

• Published in: Journal of the American Chemical Society Vol. 125; no. 21; pp. 6422 - 6427
• Main Authors: Jenkins, Cara L, Bretscher, Lynn E, Guzei, Ilia A, Raines, Ronald T
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.05.2003; Amer Chemical Soc
• Subjects: Biological and medical sciences; Chemistry; Chemistry, Multidisciplinary; Collagen - chemical synthesis; Collagen - chemistry; Conformational dynamics in molecular biology; Fundamental and applied biological sciences. Psychology; Hydroxyproline - chemistry; Models, Molecular; Molecular biophysics; Physical Sciences; Protein Conformation; Protein Structure, Secondary; Science & Technology; Structure-Activity Relationship; DISEASES; CONFORMATIONAL STABILITY; MODEL PEPTIDES; TRIPLE-HELICAL PEPTIDES; CRYSTAL-STRUCTURE; INSIGHTS; Acidity constant; Molecular structure; Biomimetic compound; Conformational dynamics; Circular dichroism spectrometry; Chemical stability; Molecular dynamics method; Triple helical structure; Theoretical study; NMR spectrometry; Chemical properties; Experimental study
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja034015j

Collagen is an integral part of many types of connective tissue in animals, especially skin, bones, cartilage, and basement membranes. A fibrous protein, collagen has a triple-helical structure, which is comprised of strands with a repeating Xaa-Yaa-Gly sequence. l-Proline (Pro) and 4(R)-hydroxy-l-proline (4-Hyp) residues occur most often in the Xaa and Yaa positions. The 4-Hyp residue is known to increase markedly the conformational stability of a collagen triple helix. In natural collagen, a 3(S)-hydroxy-l-proline (3-Hyp) residue occurs in the sequence:  3-Hyp-4-Hyp-Gly. Its effect on collagen stability is unknown. Here, two host−guest peptides containing 3-Hyp are synthesized:  (Pro-4-Hyp-Gly)3-3-Hyp-4-Hyp-Gly-(Pro-4-Hyp-Gly)3 (peptide 1) and (Pro-4-Hyp-Gly)3-Pro-3-Hyp-Gly-(Pro-4-Hyp-Gly)3 (peptide 2). The 3-Hyp residues in these two peptides diminish triple-helical stability in comparison to Pro. This destabilization is small when 3-Hyp is in the natural Xaa position (peptide 1). There, the inductive effect of its 3-hydroxyl group diminishes slightly the strength of the interstrand 3-HypCO···HNGly hydrogen bond. The destabilization is large when 3-Hyp is in the nonnatural Yaa position (peptide 2). There, its pyrrolidine ring pucker leads to inappropriate mainchain dihedral angles and interstrand steric clashes. Thus, the natural regioisomeric residues 3-Hyp and 4-Hyp have distinct effects on the conformational stability of the collagen triple helix.