Abstract
Collagen forms a characteristic triple helical structure and plays a central role for stabilizing the extra-cellular matrix. After a C-terminal nucleus formation folding proceeds to form long triple-helical fibers. The molecular details of triple helix folding process is of central importance for an understanding of several human diseases associated with misfolded or unstable collagen fibrils. However, the folding propagation is too rapid to be studied by experimental high resolution techniques. We employed multiple Molecular Dynamics simulations starting from unfolded peptides with an already formed nucleus to successfully follow the folding propagation in atomic detail. The triple helix folding was found to propagate involving first two chains forming a short transient template. Secondly, three residues of the third chain fold on this template with an overall mean propagation of ~75 ns per unit. The formation of loops with multiples of the repeating unit was found as a characteristic misfolding event especially when starting from an unstable nucleus. Central Gly→Ala or Gly→Thr substitutions resulted in reduced stability and folding rates due to structural deformations interfering with folding propagation.
Highlights
With one third of human proteins, collagen is the most abundant protein of our body
Sequence variants are known in different collagens that are associated with several human diseases like Osteogenesis Imperfecta[6], Ehlers-Danlos syndromes[7], Alport syndrome[8,9] and many others
In order to study the propagation during Molecular Dynamics (MD) simulations we added an artificial harmonic restraint to the two residues at the C-terminus of each strand to keep this nucleus on average reasonably close to the structure in a folded reference triple helix
Summary
With one third of human proteins, collagen is the most abundant protein of our body. It appears in many different tissue types like skin, cartilage, bone or hair and plays an essential role for the stability of the extracellular matrix and whole body.[1]. The characteristic feature of collagens is a parallel right-handed triple helical structure which was already proposed by Ramachandran and Kartha [2], Rich and Crick [3], and Cowan and coworkers [4]. It consists of three polypeptide chains, that form a left-handed poly-proline II-type helical coil. For this conformation it is important that every third residue is a glycine (Gly)[5] resulting in the characteristic Gly-X-Y repeating unit with X and Y mostly representing proline (Pro) or hydroxyproline (Hyp). The subsequent propagation step is too fast to be measured by the fastest available kinetic mixing experiments [12], propagation (with all-trans Pro) must happen in a time regime significantly below 1 ms
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