Energetic funnel facilitates facilitated diffusion

Abstract

Transcription factors (TFs) are able to associate to their binding sites on DNA faster than the physical limit posed by diffusion. Such high association rates can be achieved by alternating between three-dimensional diffusion and one-dimensional sliding along the DNA chain, a mechanism-dubbed facilitated diffusion. By studying a collection of TF binding sites of Escherichia coli from the RegulonDB database and of Bacillus subtilis from DBTBS, we reveal a funnel in the binding energy landscape around the target sequences. We show that such a funnel is linked to the presence of gradients of AT in the base composition of the DNA region around the binding sites. An extensive computational study of the stochastic sliding process along the energetic landscapes obtained from the database shows that the funnel can significantly enhance the probability of TFs to find their target sequences when sliding in their proximity. We demonstrate that this enhancement leads to a speed-up of the association process.

Lessons from equilibrium statistical physics regarding the assembly of protein complexes

“…Second, it is highly plausible that the energy landscape for protein-protein interactions itself might have evolved to facilitate the kinetics of protein complex assembly. This is similar to the arguments given for other classical discrimination phenomena in biology, such as the discrimination of correct initiation DNA sites by transcription factors (25,26). A third possible mechanism to prevent formation of chimeric structures is the usage of nonpairwise protein interactions, for example, allostery.…”

Guided nuclear exploration increases CTCF target search efficiency

“…This model significantly changes the view on the mechanism of target search and protein localization in mammalian cells from the facilitated diffusion picture from bacteria. Guided search has also been observed in bacterial protein-DNA-binding sites, which tend to be flanked by AT-rich DNA, serving as an "energetic funnel" guiding proteins to their target sites 48 . Similarly, upon infection of human cells with Herpes Simplex Virus, RNA Pol II becomes enriched in viral replication compartments, where its diffusion becomes anisotropic 6 .…”

Computational approaches to macromolecular interactions in the cell

“…The validity of the low-resolution approach to macromolecular recognition is well-established. It is based on the fundamental characteristics of the intermolecular energy landscape, such as the binding funnel in proteinprotein [12] and protein-nucleic acid [13] interactions, and the distribution of energy basins correlated with experimentally-observed binding modes [14]. The large-scale features of the intermolecular energy landscape are phenomenologically reflected in the macrostructural recognition characteristics of macromolecules -structural complementarity of proteins deprived of atom-size features and the anisotropy of the protein shape [11].…”

“…Protein-DNA recognition factors were also elucidated by comparing results from all-atom molecular dynamics and simulations based on simplified protein models [60]. Characteristics of the energy landscape, including the binding funnel, provide guidance for the development of computational approaches [13]. Coarse-graining is important for large-scale structural modeling of DNA and its interactions [61].…”