Mechanics of DNA
Dr. Todd Lillian
My research goes beyond the static structure of DNA and considers how the mechanical properties and dynamics of DNA influence its function. Spanning about 2cm in length and only 2nm in diameter, individual human DNA molecules are very long and flexible. Consequently, a DNA molecule’s conformation is continuously changing in response to essential forces induced by cellular processes (e.g., transcription) and thermal energy. Interestingly, the mechanical state of DNA has been shown to play a significant role in gene regulation. Unfortunately, however, our current understanding of how the mechanics and dynamics of DNA molecules influence their function is very limited. Understanding this key relationship will not only deepen our understanding of the molecule, but will enable us to develop novel therapies for diseases.
My approach to understanding the mechanics and dynamics of DNA has been to develop and utilize computational models for DNA. The disparate scales of a DNA molecule’s length and diameter create a significant computational modeling challenge. Therefore, I have focused on representing the long−length and long−time scale dynamics of DNA while sacrificing resolution of the fast vibrations of its individual atoms. In particular, I have applied an elastic rod model to represent DNA in two biologically relevant systems detailed below:
- Gene Regulation by Lac Repressor
The lac repressor protein in the bacteria E. Coli is a paradigm for gene regulation and is known as a genetic switch. In response to biochemical signals, it prevents local gene transcription by simultaneously binding two specific sites on a DNA molecule and thereby forming a loop of the intervening DNA. Although, the structure of the lac repressor protein has been determined by x−ray crystallography, the topology and energetics of the loop remain unknown. Understanding the energetic cost of loop formation is a key to understanding this gene regulatory system. To this end, I have employed a computational elastic rod model to explore loops formed from a large family of DNA sequences with differing lengths and intrinsic curvatures. The results of these computations have motivated an exciting collaboration with the Kahn lab at the University of Maryland to experimentally test my model predictions.
- Supercoil Relaxation by Topoisomerase I
Long flexible DNA molecules (~2 cm in length), are compacted into the confines of human cell nuclei (~5 μm in diameter); and as a result of this and other cellular processes, DNA molecules become interwound. Topoisomerase I enzymes are responsible for regulating the accumulation of these DNA supercoils. They function by:
- locally breaking a single backbone of the double helix
- allowing the DNA to relieve torsional stress
- repairing the broken backbone