%0 Book Section %1 statphys23_0975 %A Mirny, L.A. %A Slutsky, M. %A Wunderlich, L.A. %B Abstract Book of the XXIII IUPAP International Conference on Statistical Physics %C Genova, Italy %D 2007 %E Pietronero, Luciano %E Loreto, Vittorio %E Zapperi, Stefano %K diffusion disorder interactions jamming protein protein-dna statphys23 structure topic-10 %T How does a protein find its site on DNA? %U http://st23.statphys23.org/webservices/abstract/preview_pop.php?ID_PAPER=975 %X Recognition and binding of specific sites on DNA by transcription factors is central to regulation of gene expression. To locate its specific site on DNA, not only must a transcription factor (TF) recognize it amongst the $10^6$-$10^9$ of alternative sequences, it must do so in mere seconds within the crowded environment of cell, and further hampered by fluctuations, DNA compaction, and a myriad of other obstacles. Here we propose a model that takes into account spatial (3D) diffusion and sliding (1D) diffusion on DNA (see Fig.1). In contrast to previous studies our model takes into account disordered (sequence-specific) energy of protein-DNA interactions. We demonstrate that the disorder leads to a significant slow-down making the overall search process prohibitively slow. We propose that proteins can overcome this slowdown by being flexible and having (at least) two distinct conformations: one in which the disorder is diminished and sliding is efficient, and the other conformation that provides tight sequence-specific binding. We consider several mechanisms of coupling between the conformational transition and sliding. We propose kinetic pre-selection model that is able to provide rapid search. These observations explain widespread flexibility in DNA-binding proteins and are in good agreement with recent NMR studies of TFs. We also examine how the search process is affected by other proteins bound to DNA. Our analytical and simulations demonstrate the presence of the jamming regime. We find that proteins bound to DNA in the proximity of the specific site can (i) significantly increase the time it takes for the protein to find its site, and (ii) simultaneously increase the time a protein spends on its site. These results have several biological implications, suggesting that jamming may play a role in the assembly of protein complexes on eukaryotic enhancers and promoters.

@incollection{statphys23_0975, abstract = {Recognition and binding of specific sites on DNA by transcription factors is central to regulation of gene expression. To locate its specific site on DNA, not only must a transcription factor (TF) recognize it amongst the $10^6$-$10^9$ of alternative sequences, it must do so in mere seconds within the crowded environment of cell, and further hampered by fluctuations, DNA compaction, and a myriad of other obstacles. Here we propose a model that takes into account spatial (3D) diffusion and sliding (1D) diffusion on DNA (see Fig.1). In contrast to previous studies our model takes into account disordered (sequence-specific) energy of protein-DNA interactions. We demonstrate that the disorder leads to a significant slow-down making the overall search process prohibitively slow. We propose that proteins can overcome this slowdown by being flexible and having (at least) two distinct conformations: one in which the disorder is diminished and sliding is efficient, and the other conformation that provides tight sequence-specific binding. We consider several mechanisms of coupling between the conformational transition and sliding. We propose {\it kinetic pre-selection} model that is able to provide rapid search. These observations explain widespread flexibility in DNA-binding proteins and are in good agreement with recent NMR studies of TFs. We also examine how the search process is affected by other proteins bound to DNA. Our analytical and simulations demonstrate the presence of the jamming regime. We find that proteins bound to DNA in the proximity of the specific site can (i) significantly increase the time it takes for the protein to find its site, and (ii) simultaneously increase the time a protein spends on its site. These results have several biological implications, suggesting that jamming may play a role in the assembly of protein complexes on eukaryotic enhancers and promoters.}, added-at = {2007-06-20T10:16:09.000+0200}, address = {Genova, Italy}, author = {Mirny, L.A. and Slutsky, M. and Wunderlich, L.A.}, biburl = {https://www.bibsonomy.org/bibtex/2898ba015c3e6ea4c0372131d22dfa1c4/statphys23}, booktitle = {Abstract Book of the XXIII IUPAP International Conference on Statistical Physics}, editor = {Pietronero, Luciano and Loreto, Vittorio and Zapperi, Stefano}, interhash = {11a36e6872fde5062df55d7087ec7a20}, intrahash = {898ba015c3e6ea4c0372131d22dfa1c4}, keywords = {diffusion disorder interactions jamming protein protein-dna statphys23 structure topic-10}, month = {9-13 July}, timestamp = {2007-06-20T10:16:36.000+0200}, title = {How does a protein find its site on DNA?}, url = {http://st23.statphys23.org/webservices/abstract/preview_pop.php?ID_PAPER=975}, year = 2007 }