NMR to elucidate protein-DNA interaction

Determining exactly how proteins connect with specific DNA sequences in human cells has eluded researchers and scientists for years. While it has been possible to record the speed at which a protein could bond with DNA, little was known about how proteins located and connected with a specific pattern of DNA to allow genes to express themselves in the form of traits such as facial appearance, hair and eye color or behaviors.

In the July 16 issue of the journal Science, Rutgers-Newark chemistry professor Babis Kalodimos offers a solution to this puzzle in his paper, “Structure and Flexibility Adaptation in Nonspecific and Specific Protein-DNA Complexes.” Kalodimos’ findings may be the clue researchers need to develop future methods to inhibit the expression of certain genes that may pre-dispose individuals to harmful diseases such as cancer and Alzheimer’s disease.

Through the use of the nuclear magnetic resonance (NMR) spectroscopy, Kalodimos and his co-workers were able to determine how proteins slide along the lengthy strands forming the helix structure of DNA until they reach their intended destination – a specific DNA sequence. More important, they illustrated in detail how proteins single out their partner DNA out of millions of non-functional ones.

To better understand the scope of the question facing researchers, consider that billions of DNA codes exist within an individual’s genetic make-up and the protein must work its way through millions of non-specific DNA sequences in order to locate the correct connection.

DNA (Deoxyribonucleic acid) is a chemical structure that forms chromosomes. Structurally, DNA is a double helix made up of two strands of genetic material spiraled around each other. Each strand contains a sequence of bases (also called nucleotides). A base is one of four chemicals (adenine, guanine, cytosine and thymine). The two strands of DNA are connected at each base, but each base will only bond with one other specific base. For example, Adenine (A) will only bond with thymine (T), and guanine (G) will only bond with cytosine (C).

“We know that any protein binds first with any irrelevant DNA sequence, but the interaction is weak. It searches for the correct sequence by sliding along the DNA until it can bind with a specific DNA sequence and form a complex,” Kalodimos explained. “This helps us begin to complete the story of how proteins and DNA find each other in a very fast and accurate way. It provides us with a classical model for understanding protein-DNA interaction and offers valuable information about how transcription can be modulated at the gene level.”