Abstract
Collagen is an abundant component of the extracellular matrix and connective tissues. Some collagen-mimetic peptides (CMPs) that do not form homotrimers can anneal to damaged tissue. Here, through a computational screen, we identify (flpHypGly)7 as an optimal monomeric CMP for heterotrimer formation. We find that (flpHypGly)7 forms stable triple helices with (ProProGly)7 but not with itself. The nonnatural amino acid HflpOH, which is (2S,4S)-4-fluoroproline, is not toxic to human fibroblasts or keratinocytes. Conjugation of (flpHypGly)7 to a fluorescent dye enables the facile detection of burned collagenous tissue with high specificity. The ubiquity of collagen and the prevalence of injuries and diseases that disrupt endogenous collagen suggests widespread utility for this approach.
Highlights
Collagen—the basic building block of the extracellular matrix (ECM)—is the most abundant protein in vertebrates
Some collagenmimetic peptides (CMPs) that do not form homotrimers can anneal to damaged tissue
Its continual remodeling impacts and controls cell differentiation and proliferation,[2] and atypical organization of the collagen matrix is a biomarker for various diseases, including fibrosis, connective tissue disorders, and cancer.[3,4,5,6,7]
Summary
Collagen—the basic building block of the extracellular matrix (ECM)—is the most abundant protein in vertebrates. Is the most common triplet in collagen (10.5%).[9] These natural preferences at the Xaa and Yaa positions promote the conformational stability of the collagen triple helix.[1]. Substituents at the 4-position of a proline residue can enforce the preferred pyrrolidine-ring pucker via a gauche[10] or steric[11] effect, lowering the entropic cost for forming a triple helix and increasing its conformational stability (Table 1).[1] For example, the stereospecific installation of a fluoro group generates a gauche effect that leads to a Cγ-endo pucker in (2S,4S)-4-fluoroproline (flp) and supports the Cγ-exo pucker in (2S,4R)-4-fluoroproline (Flp) to a greater extent than does the 4R-hydroxy group of Hyp.[12,13,14] The impact of such substitutions are apparent in the thermostability of collagen-mimetic peptides (CMPs).
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