Changes in browsing habits for the purpose of searching for DNA fragments

What did a protein molecule go through before it folded into the final and active structure? How does the "history" of the protein affect its activity? How do proteins search for their binding sites on the DNA helix before they attach to it? These things are researched by Dr. Kobi Levy from the Weizmann Institute

Every good detective who is required to solve a mystery knows that the findings collected at the crime scene itself are not enough, and that he must build a complete and detailed picture as possible of the events that preceded it. Seemingly marginal events, remote in place and time, may prove to have a profound and decisive impact. Researchers deciphering biological mysteries also generally need to stay away from the flashlight. The key to the solution often lies in unexpected places - in the "moment before", and in so-called side events. What did a protein molecule go through before it folded into the final and active structure? How does the "history" of the protein affect its activity? How do proteins search for their binding sites on the DNA helix before they attach to it?

These are several examples of the questions that preoccupy Dr. Kobi Levy, from the Department of Structural Biology at the Weizmann Institute of Science. Dr. Levy uses computational models and other theoretical tools to study biological systems, which he approaches from a chemical-physical point of view. The simplified models he creates present in a minimalist way
Complex biological phenomena, in order to explain how proteins and other large biological molecules, such as DNA and RNA, work and function. Dr. Levy hopes that this research will shed light on fundamental and essential biological processes, and will help in understanding the causes of disruptions in the structure and function of these molecules - disruptions that are responsible for a long list of diseases, including neurodegenerative diseases of the nervous system and cancer.

One of the questions investigated in Dr. Levy's laboratory focuses on the changes that go through binding to its amino acid skeleton - and being removed from it. It is known that these changes affect the function of the protein - they constitute a "switch" that activates and deactivates its activity, and also regulates the intensity of the activity. But do they also affect the identity of the protein and its properties? A study recently published in the journal "Records of the National Academy of Sciences of the USA" (PNAS) shows that linking sugar molecules to a protein affects its stability. Dr. Levy and the post-doctoral researcher from his group, Dr. Dalit Shantal-Bachor, created a simple model of a protein, in which each amino acid is represented by a single bead.
After that, they attached two types of sugar molecules to the protein skeleton in varying positions and amounts, creating about 60 versions of the original protein. The results obtained using the model agreed with the experimental results, according to which the thermodynamic and kinetic stability of the protein increased with the increase in the amount of sugar molecules.

Later, the researchers used the model to understand why the stability of the glycated protein increases. Contrary to the intuitive assumption that the sugars increase the stability of the folded structure of the protein, the researchers were surprised to discover that the answer lies precisely in the phase before folding - the sugars increase the instability of the unfolded structure, thus "encouraging" it to fold. "The chemical changes that proteins undergo, such as the addition of sugar or phosphorus groups, enrich their properties beyond those determined by the amino acid sequence.

They can be seen as an economical way developed by nature to considerably increase the protein pool. "Deciphering the code contained in the sequence of amino acids and the interrelationship with the chemical changes that the protein undergoes during its life in the cell is necessary for understanding the function of proteins," says Dr. Levy. "In nature, the sugars function as a kind of regulator that determines how much of the protein will be in the folded state, and how much will be in the unfolded state." In the future, he plans to use similar manipulations to increase the stability of proteins using another material - polyethylene glycol. This substance is used in the biotechnology industry to extend the shelf life of proteins, and understanding the principles underlying this phenomenon will help create more durable proteins. This is a complex problem, since not only the amount of the substance has an effect, but also the location where it binds to the protein skeleton. The definition of the suitable sites for binding polyethylene-glycol may vary from protein to protein, but Dr. Levy hopes that it will be possible to formulate general principles for determining the most suitable sites.

Another field that Dr. Levy examines through his models is the interrelationships between proteins and DNA coils. Linking protein molecules to unique sites on the DNA is a condition for essential biological processes such as gene expression, DNA damage repair, and DNA "packaging" in a compact structure. Such a link requires a combination of speed and precision - the proteins manage to find the right site, out of a million to a billion possibilities, within a period of time ranging from one second to ten seconds. How do they do it? In a study recently published in the Journal of Molecular Biology, Dr. Levy and research student Ohad Givati ​​created a model that examines the possible "search methods": one option is a thorough and precise scan, base by base, of the DNA sequence.

Another option is random sampling of the sequence while quickly skipping the coil and jumping between adjacent coils. The model showed that the protein moves on the DNA coil in a spiral fashion, and that the most efficient search consists of 80% skipping and 20% gliding along the DNA, a combination that guarantees both fast and accurate scanning. Later, the researchers will use the model to investigate other questions related to the interactions between protein and DNA, such as, for example, the differences between a double-stranded molecule and a single-stranded molecule, and the "surfing habits" of protein clusters.

personal

Kobi Levy was born in Tel Aviv in 1972. In 1994 he received a bachelor's degree in chemistry from the Technion, and in 2002 he completed his doctoral studies in theoretical-computational biophysics at Tel Aviv University. He then embarked on post-doctoral research at the Center for Theoretical Biological Physics at the University of San Diego, and in 2006 he returned to Israel and joined the structural biology department at the institute as a senior researcher.

At the same time as his scientific work, Dr. Levy is interested in various aspects of education and teaching - during his studies he worked as a chemistry teacher at a high school in Haifa, and later became a member of the faculty of the Center for Teaching Improvement at Tel Aviv University. He is currently a member of the executive committee of the "Daniel Association" - an association of parents from the anthroposophical community for the promotion of education in the Waldorf approach. The association founded and operates educational frameworks with this approach in Nes-Ziona. Dr. Levy lives in Rehovot, is married to Rinat, and is the father of Naama (about eight years old) and Arnon (about two years old).