Premeltons in DNA

The author is internationally renowned for his pioneering contributions to the understanding of how the anticancer agent, actinomycin D, binds to DNA and exerts its mechanism of action. Using the technique of X-ray crystallography, he and his research colleague, Shri C. Jain, solved the structure of a crystalline complex containing actinomycin and deoxyguanosine in the early 1970's, and this information led them to propose a model that is now widely accepted to understand the general

features of how actinomycin binds to DNA.

According to this model, the phenoxazone ring system on actinomycin intercalates between adjacent base pairs, while pentapeptide chains lie in the narrow groove of the B- helix, forming hydrogen bonds (in the case of d (pGpC) sequences) with guanine residues on opposite chains. Although X-ray crystallographic studies of actinomycin complexed to a number of different self-complementary oligonucleotides have now confirmed the overall features of this model, the precise nature of the DNA conformation remains unknown due to problems inherent in refining large structures with limited resolution data. Implicit in the original model was the assumption that actinomycin binds to B-DNA or to a distorted form of B-DNA. The possibility that actinomycin might bind to some other discretely different DNA conformational state was not envisioned at that time.

Together with his research team, Dr. Sobell continued to extend his crystallographic studies to include other intercalators (these contain a diverse variety of heterocyclic ring systems) complexed to a number of different self-complementary DNA and RNA dinucleotides. The information obtained from these studies led him to propose the existence of beta-DNA, a metastable and hyperflexible DNA form, a form very different from the Watson-Crick B- and A- structures, which he believes, are intimately associated with the intercalation process. The existence of this beta-DNA structure required modification to the original actinomycin-DNA binding model. When combined with the realization that beta-DNA is an obligatory structural intermediate (i.e., transition-state intermediate) in the unwinding of duplex DNA leading to melting, this novel beta-DNA binding model leads to understanding the mechanism of action of actinomycin.

This book calls attention to the wider repercussions this modified actinomycin-DNA binding model has had in understanding much of DNA physical chemistry and molecular biology. These stem from additional insights provided by another more recent area of inquiry known as Nonlinear Science.