Conformational Stability of Collagen Relies on a Stereoelectronic Effect

Bretscher, Lynn E.; Jenkins, Cara L.; Taylor, Kimberly M.; DeRider, Michele L.; Raines, Ronald T.

doi:10.1021/ja005542v

Cited by 425 publications

(550 citation statements)

References 22 publications

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“…In previous work, we demonstrated how to use stereoelectronic effects to produce collagen triple helices that have greater conformational stability than any found in nature (30,44,45). Here, we have complemented that work by demonstrating how to use molecular self-assembly to produce collagen triple helices that are longer than any found in nature.…”

Section: Resultsmentioning

confidence: 62%

Self-assembly of synthetic collagen triple helices

Kotch

Raines

2006

Proc. Natl. Acad. Sci. U.S.A.

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Collagen is the most abundant protein in animals and the major component of connective tissues. Although collagen isolated from natural sources has long served as the basis for some biomaterials, natural collagen is difficult to modify and can engender pathogenic and immunological side effects. Collagen comprises a helix of three strands. Triple helices derived from synthetic peptides are much shorter (<10 nm) than natural collagen (Ϸ300 nm), limiting their utility. Here, we describe the synthesis of short collagen fragments in which the three strands are held in a staggered array by disulfide bonds. Data from CD spectroscopy, dynamic light scattering, analytical ultracentrifugation, atomic force microscopy, and transmission electron microscopy indicate that these ''sticky-ended'' fragments self-assemble via intermolecular triple-helix formation. The resulting fibrils resemble natural collagen, and some are longer (>400 nm) than any known collagen. We anticipate that our self-assembly strategy can provide synthetic collagen-mimetic materials for a variety of applications.biomaterial ͉ coiled-coil ͉ nanotechnology ͉ cystine knot ͉ peptide C ollagen constitutes one-third of the human proteome, including three-quarters of the dry weight of human skin. Its high natural abundance and intrinsic plasticity have spurred the development of collagen as a biomaterial (1, 2). The most common source of clinical collagen is now Bos taurus, the domestic cow. Unfortunately, bovine collagen can illicit deleterious pathological and immunological effects when transplanted into humans (3-5). Moreover, the preparation of enriched solutions of natural collagen is problematic (6), and its sitespecific covalent modification is not feasible. We suspected that synthetic chemistry could offer a solution to these problems.The quaternary structure of collagen comprises three strands that wrap around one another to form a triple helix (7). Each strand has the repeating sequence XaaYaaGly, with the most abundant triplet being ProHypGly [Hyp ϭ (2 S,4R)-4-hydroxyproline] (8). The folding of (XaaYaaGly) nՅ10 peptides into blunt-ended triple helices has been investigated thoroughly (7). Although such triple helices are biomaterial candidates (9-12), they are limited to the length of a synthetic peptide (Ͻ10 nm), which is much shorter than natural collagen (Ϸ300 nm). The polymerization of (XaaYaaGly) 10 peptides has afforded long strands that adopt triple-helical structure but have high polydispersity (13).Molecular self-assembly underlies the ''bottom-up'' approach to macromolecular design, wherein a desirable structure forms spontaneously through noncovalent interactions (14, 15). Selfassembling peptides and proteins have been designed to serve as materials for biological and nanotechnological applications (16,17). Using the self-assembly approach, Woolfson and coworkers (18,19) have produced fibers with a design based on a dimeric coiled-coil structure. Likewise, fibrous peptides based on the natural protein elastin (20) and de novo building b...

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Section: Resultsmentioning

confidence: 62%

Self-assembly of synthetic collagen triple helices

Kotch

Raines

2006

Proc. Natl. Acad. Sci. U.S.A.

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285

232

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“…30,31 For example, replacing Hyp with (2S,4R)-4-fluoroproline (Flp), which has the native-like stereochemistry, but not (2S,4S)-4-fluoroproline (flp) results in triple helices with markedly enhanced stability (Table I). [32][33][34] This and other results revealed that a gauche effect in Hyp and Flp mandates a C γ -exo pucker in the pyrrolidine ring, 34,35 which preorganizes the φ, ψ, and ω dihedral angles to those required for triple-helix assembly. 34,36 (2S,4S)-4-Methylproline (Mep) achieves the same end by manifesting a steric rather than stereoelectronic effect ( Figure 1 ; Table I).…”

Section: Introductionmentioning

confidence: 55%

“…[32][33][34] This and other results revealed that a gauche effect in Hyp and Flp mandates a C γ -exo pucker in the pyrrolidine ring, 34,35 which preorganizes the φ, ψ, and ω dihedral angles to those required for triple-helix assembly. 34,36 (2S,4S)-4-Methylproline (Mep) achieves the same end by manifesting a steric rather than stereoelectronic effect ( Figure 1 ; Table I). 31 (The pyrrolidine ring of proline actually prefers two distinct twist, rather than envelope, conformations.…”

Section: Introductionmentioning

confidence: 55%

“…Proline itself has a slight preference for the C γ -endo ring pucker, and K trans/cis = 4.6 in water. 34 Our group has shown that the minimum-energy conformation of 4-substituted derivatives of proline with K trans/cis > 4.6 is generally a C γ -exo ring pucker, whereas those with K trans/cis ≤ 4.6 typically prefer a C γ -endo ring pucker. 35 Using 13 C NMR spectroscopy, we determined that K trans/cis = 5.4 for Ac-Clp-OMe (10) and 2.2 for Ac-clp-OMe (9).…”

Section: Ring Pucker and K Trans/cis Of Clp And Clpmentioning

confidence: 99%

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4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

2007

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Collagen is an abundant, triple-helical protein comprising three strands of the repeating sequence: Xaa-Yaa-Gly. (2S)-Proline and (2S,4R)-4-hydroxyproline (Hyp) are common in the primary structure of collagen. Here, we use nonnatural proline derivatives to reveal determinants of collagen stability. Specifically, we report high-yielding syntheses of (2S,4S)-4-chloroproline (clp) and (2S, 4R)-4-chloroproline (Clp). We find that the crystal structure of Ac-Clp-OMe is virtually identical to that of Ac-Hyp-OMe. In contrast, the conformational properties of Ac-clp-OMe are similar to those of Ac-Pro-OMe. Ac-Clp-OMe has a stronger preference for a trans amide bond than does Ac-ProOMe, whereas Ac-clp-OMe has a weaker preference. (Pro-Clp-Gly) 10 forms triple helices that are significantly more stable than those of (Pro-Pro-Gly) 10 . Triple helices of (clp-Pro-Gly) 10 have stability similar to those of (Pro-Pro-Gly) 10 . Unlike (Pro-Clp-Gly) 10 and (clp-Pro-Gly) 10 , (clpClp-Gly) 10 does not form a stable triple helix, presumably due to a deleterious steric interaction between proximal chlorines on different strands. These data, which are consistent with previous work on 4-fluoroprolines and 4-methylprolines, support the importance of stereoelectronic and steric effects in the stability of the collagen triple helix and provide another means to modulate that stability.

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“…Besides this, the puckering preferences of proline and its derivatives have been studied extensively, 4,9,10,27 not only because they strongly correlate with the backbone φ-ψ angles, but also because they can affect the conformations of the electronegative substituents and the trans/cis ratio. 4,10,28 In addition, other factors may also influence the collagen stability, such as the steric effects, 12,29 the hydration effects, 30 the contributions from the unfolded state, 31 etc. To date, the published results are very informative (for review, see Ref.…”

Section: Implications For Collagen Stabilitymentioning

confidence: 99%

Proline puckering parameters for collagen structure simulations

2015

AIP Advances

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The puckering free-energy surface of proline AIP Advances 3, 032141 (2013) Collagen is made of triple helices rich in proline residues, and hence is influenced by the conformational motions of prolines. Because the backbone motions of prolines are restricted by the helical structures, the only side chain motion-proline puckering-becomes an influential factor that may affect the stability of collagen structures. In molecular simulations, a proper proline puckering population is desired so to yield valid results of the collagen properties. Here we design the proline puckering parameters in order to yield suitable proline puckering populations as demonstrated in the experimental results. We test these parameters in collagen and the proline dipeptide simulations. Compared with the results of the PDB and the quantum calculations, we propose the proline puckering parameters for the selected collagen model simulations. C 2015 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 Unported License.

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Conformational Stability of Collagen Relies on a Stereoelectronic Effect

Cited by 425 publications

References 22 publications

Self-assembly of synthetic collagen triple helices

Self-assembly of synthetic collagen triple helices

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

Proline puckering parameters for collagen structure simulations

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