The stabilisation of collagen fibres during development and through growth to maturation is now fairly well understood. It is a carefully controlled enzymic process which produces intermolecular cross-links at specific locations. In marked contrast, the changes in the physical properties that occur towards old age are stochastic and involve oxidative reactions that result in the formation of glucose mediated cross-links. This excessive and random cross-linking leads to a devastating loss of tissue functionality and deterioration of vital organs. In addition, specific residues involved in cell-matrix interactions may become modified. This can affect the expression of cells and lead to the formation of an inappropriate collagen matrix during its slower turnover in old age. This is exemplified in the ubiquitous disorders osteoporosis and osteoarthritis, age-related diseases in which we have noted gene regulated changes in the collagen deposited and also post-translational changes such as over-hydroxylation of lysine residues. Both of these effects can have a profound deleterious effect on the function of the matrix tissue.

We have recently re-examined the characteristic sharp denaturation temperature of the collagen molecule and fibre. It has been generally accepted for many years that denaturation is an equilibrium process involving the rupture of hydrogen bonds. We have now proposed that the process is an irreversible rate process, in which uncoupling of thea-chains initially occurs in a thermally labile domain devoid of hydroxyproline. The domain is located near the C-terminal and following alignment of the molecules in the quarter-stagger-end-overlap arrangement is located in the gap region of the fibre. The domain appears to be conserved in type I of several animal species, and is present in types II and III. Collagen molecules that co-polymerise to form fibres, types V and XI, do not possess this labile domain.

Ramachandran proposed that stabilisation of the triple helix occurred through hydrogen-bonded water-bridges involving the hydroxyl group of hydroxyproline. Recent studies have been equivocal, some questioning the role of water bridges and of hydroxyproline, whilst recent detailed X-ray studies of collagen-like peptides demonstrate the presence of a stabilising sheath of hydrogen-bonded water. Our findings support the proposal of hydrogen-bonded water-bridges stabilising the triple helix.