March 14, 2003

Francis Crick
The Salk Institute
La Jolla, CA

Dear Francis:

Many years ago (in the fall of 1971), after giving a seminar at King's College on actinomycin binding to DNA, Maurice asked me to join him in his office to discuss intercalation. He immediately stated that, although he always believed that the concept of intercalation was correct, he couldn't understand how this would happen. "After all, no space exists between the base-pairs in either B- or A- DNA. DNA had to have another more open structure, even if it existed only transiently, for a drug molecule to be able to slip in-between the base-pairs".

I later realized that Maurice was attempting to understand intercalation as a manifestation of "DNA breathing", and that he suspected another DNA structural form to be involved.

I had a similar experience with Max. Max came to visit me in Rochester (for a week in 1976 to give a series of lectures in protein crystallography). After he returned to England, I received a letter from him congratulating us on our crystallographic work, and mentioning that he looked forward to us "nailing down the mechanism to understand how drugs and dyes intercalate into DNA". I understood his letter to mean that he thought our structural studies would lead us to eventually understand not only the structures of a variety of intercalation complexes, but, more importantly, to understand the actual mechanism of intercalation.

So, there were really two questions that had to be resolved. Did DNA have another structure (i.e., other than B-DNA) to explain intercalation? If it did, how did this other structure arise and how was it related to DNA "breathing"?

In these early days, we were in "full swing" with our crystallographic studies of drugs binding to self-complementary dinucleoside monophosphates. We eventually solved a total of 14 separate crystal structures involving 7 different intercalators. In all but one (proflavine), we observed the beta-structural element "pinned" by the intercalator.

These data led me to propose the beta-DNA structure (a structure that readily explains "neighbor exclusion" intercalative drug binding), and this, in turn, has led me to propose a mechanism to understand how drugs and dyes intercalate into DNA.

I would have been very content to have "stopped" at this point. However, by its very nature, my intercalation model forces me to open a much wider chapter in molecular biology. Topics such as the nuclease hypersensitive sites in naked DNA and in chromatin, gene activation, the conformation of DNA in active genes, protein-DNA melting, along with a deeper understanding of the physical nature of DNA premelting and melting - are inevitably tied to my intercalation model.

You once mentioned to me that, "in order to appreciate a theory, one needs a 'head' for theory". Francis, this is your type of theory, and, I suspect, if things had been different, you might have been the one to propose it!

I am enclosing a copy of "DNA Premelting" that will appear as an entry into the "Encyclopedia of Nonlinear Science", edited by Alwyn C. Scott, Routledge, New York, London, 2005.

I would appreciate your comments.

All the best,