**8. Conclusions and future directions**

The intrinsic flexibility and dynamics of LDL lipids and protein in conjunction with the inherent compositional heterogeneity of LDL particles has hitherto hampered successful structure determinations at atomic level. Recent technological developments, however, allowed to restore characteristic structural features of individual LDL particles at low resolution. In particular, using cryo e.m. 3D-reconstruction techniques several groups have succeeded in imaging morphological and topological details of LDL to a resolution limit of approximately 2 nm [34-36]. Now, new concepts will be needed to make further progress in the development of high resolution models of LDL. One promising way is to put stronger emphasis on protein crystallography in combination with computational modelling and molecular dynamics simulations. X-ray crystallography apprears to be a hopeless pursuit with heterogeneous and flexible particles like LDL. Nevertheless, our earlier attempts of crystallisation have been partially successful [74]. Additional efforts, however, have to be focussed on the stabilization of apo-B100 in a more rigid state, perhaps by co-crystallisation with monoclonal antibodies. An alternative way ahead would be to work with lipid-free apo-B100 stabilized by detergent-mimetic systems, e.g. amphipathic designer peptides, or to proceed with truncated fragments of apo-B100.

At present there is still a deficit in our knowledge concerning the molecular lipid trafficking mechanisms of LDL. To know the atomic structure of LDL, in particular of apo-B100, may well contribute to a better understanding of biologic aspects of cardiovascular diseases, especially with respect to future strategies towards rational pharmaceutical interventions.
