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Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Session IX Abstracts
Protein-DNA Interactions: Fine Balance between High Affinity and Fast Kinetics
Yaakov (Koby) Levy
.
Weizmann Institute of Science, Rehovot, Israel.
Interactions between proteins and nucleic acids are ubiquitous and central to the life of cells. The
remarkable efficiency and specificity of protein-DNA recognition presents a major theoretical
puzzle given the size of the genome, the large number of molecular species in vivo at a given
time, and the crowded environment they inhabit. Our research is motivated at quantitatively
advancing our understanding of the kinetics and mechanisms of protein-DNA recognition, the
molecular and physical principles of fast association, and protein recruitment by DNA. For the
first time, we have visualized protein sliding along DNA where the protein binds DNA
nonspecifically and performs a helical motion when it is placed in the major groove. Using
coarse-grained models we found that the spiral motion along the sugar-phosphate rail is typical
to various DNA-binding motifs. This stochastic dynamics that is governed by electrostatic forces
has similar structural features to the specific binding mode of the protein with the DNA. In our
study, we address the question of the linkage between the molecular architecture of DNA-
binding proteins and the search mechanism. We have explored the interplay between the
molecular characteristics of the proteins (e.g., DNA recognition motifs, degree of flexibility, and
oligomeric states) and the nature of sliding, intersegment transfer events and the overall
efficiency of the DNA search. Another important aspect of the search is how the in-vivo
conditions (for example, crowding in the cell or coverage of DNA by nucleosomes) affect the
efficiency of DNA search.
