Retrospect And Prospect

Structural elucidation of the DNA-cationic lipid complexes and realization of the extent to which they share the structural features of pure DNA or pure lipid polymorphism have advanced notably in the past few years. Some old questions have been answered and new questions raised. It is these new questions that challenge our knowledge of the intricacies of interactions between macromolecules.

The DNA-lipid complexes found so far are only a sample of the much wider set of structures that will be seen on a full DNA-lipid phase diagram. We argue that this larger set of possibilities be approached by firmly established methods to measure the energies of these structures at the same time that they are determined and located on a phase diagram. Built on principles of direct molecular interactions, recognizing the consequences of thermal agitation, this line of observation and analysis can lead to an understanding of the energetic ''whys'' and preparative ''hows'' of complex structures.

Forces so delineated are already knowledgeably applied in new preparations. Precisely how the structure of DNA-lipid aggregates will affect their efficacy in transfection remains to be seen. So far, the ideas we have are too general and have been learned from studying analytically tractable but technically inadequate preparations. General principles do not lead to specific results. Molecules are too interesting to allow easy success in clinical design. Still there is little doubt of a practical link between the energy and structure of these complexes and their viability in a technological application.

Even the present general understanding of forces, even the cartoon ideas of the directions in which forces act in macromo-lecular complexes can tutor the bench scientist on how to improve preparations. There is enough known for a healthy iteration between experimental attempt and theoretical reason. Experimental successes and failures become the data for molecule force analyses. Various DNA-lipid assemblies reflect the various actions of competing forces. Molecular theorists can define and delineate these forces as they act to create each form; they can provide a logic to design variations in preparation. Basic scientists and clinicians are already in a position to help each other to improve their ways.

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