Triple‐Helix‐Stabilizing Effects in Collagen Model Peptides Containing PPII‐Helix‐Preorganized Diproline Modules

Andreas Maaßen,Isabelle Grimm,Ronald Kühne,Jörg‐Martin Neudörfl,Ulrich Baumann,Ines Neundorf,Jan M Gebauer,Hans‐Günther Schmalz,Elena Theres Abraham

doi:10.1002/ange.201914101

Abstract

AbstractCollagen model peptides (CMPs) serve as tools for understanding stability and function of the collagen triple helix and have a potential for biomedical applications. In the past, interstrand cross‐linking or conformational preconditioning of proline units through stereoelectronic effects have been utilized in the design of stabilized CMPs. To further study the effects determining collagen triple helix stability we investigated a series of CMPs containing synthetic diproline‐mimicking modules (ProMs), which were preorganized in a PPII‐helix‐type conformation by a functionalizable intrastrand C2 bridge. Results of CD‐based denaturation studies were correlated with calculated (DFT) conformational preferences of the ProM units, revealing that the relative helix stability is mainly governed by an interplay of main‐chain preorganization, ring‐flip preference, adaptability, and steric effects. Triple helix integrity was proven by crystal structure analysis and binding to HSP47.

Highlights

Collagen is the most abundant structural protein in animals, comprising a family of 28 known members differing in their composition and supramolecular assembly
To further study the effects determining collagen triple helix stability we investigated a series of Collagen model peptides (CMPs) containing synthetic diproline-mimicking modules (ProMs), which were preorganized in a polyproline II (PPII)-helixtype conformation by a functionalizable intrastrand C2 bridge
In the course of our previous studies aiming at the development of small-molecule inhibitors of the PPII helix recognizing Ena/VASP homology 1 (EVH1) domain, we developed proline-derived modules (ProMs) ProM1 and ProM2 (Figure 2).[27,28,29,30]

Summary

Introduction

Guarantees the structural integrity of vertebrates.[1,2,3] In addition, collagen interacts with numerous proteins such as cell-surface receptors or matrix metalloproteinases and is involved in processes such as cell adhesion, proliferation, and extracellular matrix regulation.[4,5] The biocompatibility and bioactivity of collagen together with advances in synthetic substitutes[6,7] open the path for biomedical applications such as bone grafts,[8,9] wound dressings,[10,11] engineering of functional tissues,[12,13] tendon repair,[14] or inhibition of diseaserelated target proteins.[4,15] In the context of diseases, pathological conditions are coined by structural defects and impaired collagen stability (e.g., osteogenesis imperfecta).[16,17] A stable structure and correct folding are of fundamental importance for molecular recognition and function of collagen. In the first two positions (Xxx and Yyy), proline (Pro, P) or (4R)-hydroxyproline (Hyp, O) are predominantly found.[1] Hyp can be introduced by prolyl-4hydroxylase-mediated functionalization of proline residues.[3] Another member of the machinery involved in the complex biosynthesis of collagen is the chaperone HSP47. This essential heat shock protein transiently and exclusively binds to triple helical collagen to stabilize its conformation.[3,19] Upon binding, an arginine–aspartate salt bridge was observed in a model system.[20]. In the course of our previous studies aiming at the development of small-molecule inhibitors of the PPII helix recognizing Ena/VASP homology 1 (EVH1) domain, we developed proline-derived modules (ProMs) ProM1 and ProM2 (Figure 2).[27,28,29,30] The design is based on the stereodefined covalent connection of two adjacent proline rings by a C2 bridge to freeze the system in a PPII-helix-type conformation

Results and Discussion

Conclusion

Conflict of interest