Book of Abstracts: Albany 2003
June 17-21 2003
How Does a Protein Find its Site on the DNA?
Complex transcription machinery in cells is regulated by a set of protein molecules - transcription factors (TFs)- whose "system-level" function can be usually formulated quite plainly as follows: I) Receive a control signal: This can be ligand binding or unbinding meaning initiation or shutting down of the transcription machinery. II) Find a specific site on the DNA and bind to it. Every TF has one or several specific sites on the DNA molecule that forming a complex with them allows or prevents the transcription, depending on the actual control mechanism. Site location should be fast (~ 1 sec) and the specific complex should be stable (Kd ~ 1e-15 - 1e-8 M).
Target location dynamics that provides the best search times, incorporates both one-dimensional diffusion ("sliding") of TFs along the DNA and three-dimensional diffusion inside the DNA globule. However, as we show, existing models of protein-DNA interaction energy cannot account for both rapid "sliding" and high stability of the specific complex. This suggests that at least two modes of protein-DNA interaction should exist - "search" and "recognition" - which occur at different protein conformations. In the search conformation, sequence-nonspecific contribution to the binding energy dominates, whereas in the recognition mode, sequence-specific energy provides the necessary stability of the complex with respect to the rest of the genome and the cytoplasm as well. Sequence-specific energy component is of essentially random character and may significantly impede the "sliding" in the search mode. However, if it is correlated with the sequence-specific energy in the recognition mode, it provides a preselection mechanism for potential specific sites, at which conformational changes occur. This preselection mechanism can provide a necessary reconciliation between fast search and high specificity.
M. Slutsky and L. Mirny
Harvard-MIT Division of Health Sciences and Technology,