The collagens are involved in numerous interactions which contribute to the form, function, physiology and pathobiology and of all connective tissues. Disturbances in the interactions of collagen contribute to pathobiological changes in oral tissues, in the skeleton and in the cardiovascular system, and if these interactions are perturbed during embryonic stages, developmental disorders can arise. In order to understand the physiology and pathobiology of collagen it is necessary to elucidate the molecular basis of the reactions of collagen. Our objective in this proposal is to elucidate the nature of the reactive sites and the physico-chemical factors that govern their reactivity. The reactive sites of collagen are distributed axially on the triple helix. Our hypothesis is that the biological specificity of these sites depends on distinct and specific molecular perspectives offered to the interacting species. A homogenous conformation extending along the entire length of the triple helix would preclude such specificity. In order for the reactive sites to express specific molecular perspectives at the approach of a ligand, these regions of the triple helix must depart at least transiently from the conformation extant in the rest of the molecule. This is supported by the observation that certain interactions of collagen are promoted by denaturing conditions. According to our hypothesis, the expression of specific reactivity depends not only on specific sequence markers, but also on differences in the inter-chain interactions that stabilize the triple helix in the reactive sites and adjacent non-reacting regions since that would facilitate the presentation of a distinct molecular perspective to an approaching ligand. We propose further that imino-rich structural sequences support the triple helical conformation to the extent that most commonly used experimental techniques reveal, and that relatively imino-sparse reactive sequences constrained in this conformation, confer specific reactivity to different sites on the collagens. We plan to elucidate this important basis of collagen function by examining the conformation of isolated sequences from structural and reactive regions of collagen, experimentally through the use of synthetic polypeptide models, and using theoretical techniques of energy and molecular mechanics and dynamics calculations and simulation of conformation. The intramolecular interactions involved in the stability of structural and reactive conformations will be determined using both experimental and theoretical procedures.
| Bhatnagar, R S; Pattabiraman, N; Sorensen, K R et al. (1988) Inter-chain proline:proline contacts contribute to the stability of the triple helical conformation. J Biomol Struct Dyn 6:223-33 |
