23 research outputs found
Genome-wide organization of eukaryotic pre-initiation complex is influenced by nonconsensus protein-DNA binding
Genome-wide binding preferences of the key components of eukaryotic
pre-initiation complex (PIC) have been recently measured with high resolution
in Saccharomyces cerevisiae by Rhee and Pugh (Nature (2012) 483:295-301). Yet
the rules determining the PIC binding specificity remain poorly understood. In
this study we show that nonconsensus protein-DNA binding significantly
influences PIC binding preferences. We estimate that such nonconsensus binding
contribute statistically at least 2-3 kcal/mol (on average) of additional
attractive free energy per protein, per core promoter region. The predicted
attractive effect is particularly strong at repeated poly(dA:dT) and
poly(dC:dG) tracts. Overall, the computed free energy landscape of nonconsensus
protein-DNA binding shows strong correlation with the measured genome-wide PIC
occupancy. Remarkably, statistical PIC binding preferences to both
TFIID-dominated and SAGA-dominated genes correlate with the nonconsensus free
energy landscape, yet these two groups of genes are distinguishable based on
the average free energy profiles. We suggest that the predicted nonconsensus
binding mechanism provides a genome-wide background for specific promoter
elements, such as transcription factor binding sites, TATA-like elements, and
specific binding of the PIC components to nucleosomes. We also show that
nonconsensus binding influences transcriptional frequency genome-wide
Sequence correlations shape protein promiscuity
We predict analytically that diagonal correlations of amino acid positions
within protein sequences statistically enhance protein propensity for
nonspecific binding. We use the term 'promiscuity' to describe such nonspecific
binding. Diagonal correlations represent statistically significant repeats of
sequence patterns where amino acids of the same type are clustered together.
The predicted effect is qualitatively robust with respect to the form of the
microscopic interaction potentials and the average amino acid composition. Our
analytical results provide an explanation for the enhanced diagonal
correlations observed in hubs of eukaryotic organismal proteomes [J. Mol. Biol.
409, 439 (2011)]. We suggest experiments that will allow direct testing of the
predicted effect
Nonspecific Transcription-Factor-DNA Binding Influences Nucleosome Occupancy in Yeast
AbstractQuantitative understanding of the principles regulating nucleosome occupancy on a genome-wide level is a central issue in eukaryotic genomics. Here, we address this question using budding yeast, Saccharomyces cerevisiae, as a model organism. We perform a genome-wide computational analysis of the nonspecific transcription factor (TF)-DNA binding free-energy landscape and compare this landscape with experimentally determined nucleosome-binding preferences. We show that DNA regions with enhanced nonspecific TF-DNA binding are statistically significantly depleted of nucleosomes. We suggest therefore that the competition between TFs with histones for nonspecific binding to genomic sequences might be an important mechanism influencing nucleosome-binding preferences in vivo. We also predict that poly(dA:dT) and poly(dC:dG) tracts represent genomic elements with the strongest propensity for nonspecific TF-DNA binding, thus allowing TFs to outcompete nucleosomes at these elements. Our results suggest that nonspecific TF-DNA binding might provide a barrier for statistical positioning of nucleosomes throughout the yeast genome. We predict that the strength of this barrier increases with the concentration of DNA binding proteins in a cell. We discuss the connection of the proposed mechanism with the recently discovered pathway of active nucleosome reconstitution
Multi-scale sequence correlations increase proteome structural disorder and promiscuity
Numerous experiments demonstrate a high level of promiscuity and structural
disorder in organismal proteomes. Here we ask the question what makes a protein
promiscuous, i.e., prone to non-specific interactions, and structurally
disordered. We predict that multi-scale correlations of amino acid positions
within protein sequences statistically enhance the propensity for promiscuous
intra- and inter-protein binding. We show that sequence correlations between
amino acids of the same type are statistically enhanced in structurally
disordered proteins and in hubs of organismal proteomes. We also show that
structurally disordered proteins possess a significantly higher degree of
sequence order than structurally ordered proteins. We develop an analytical
theory for this effect and predict the robustness of our conclusions with
respect to the amino acid composition and the form of the microscopic potential
between the interacting sequences. Our findings have implications for
understanding molecular mechanisms of protein aggregation diseases induced by
the extension of sequence repeats
DNA sequence correlations shape nonspecific transcription factor-DNA binding affinity
Transcription factors (TFs) are regulatory proteins that bind DNA in promoter
regions of the genome and either promote or repress gene expression. Here we
predict analytically that enhanced homo-oligonucleotide sequence correlations,
such as poly(dA:dT) and poly(dC:dG) tracts, statistically enhance non-specific
TF-DNA binding affinity. This prediction is generic and qualitatively
independent of microscopic parameters of the model. We show that non-specific
TF binding affinity is universally controlled by the strength and symmetry of
DNA sequence correlations. We perform correlation analysis of the yeast genome
and show that DNA regions highly occupied by TFs exhibit stronger
homo-oligonucleotide sequence correlations, and thus higher propensity for
non-specific binding, as compared with poorly occupied regions. We suggest that
this effect plays the role of an effective localization potential enhancing the
quasi-one-dimensional diffusion of TFs in the vicinity of DNA, speeding up the
stochastic search process for specific TF binding sites. The predicted effect
also imposes an upper bound on the size of TF-DNA binding motifs
Nonspecific Protein-DNA Binding Is Widespread in the Yeast Genome
Recent genome-wide measurements of binding preferences of ~200 transcription
regulators in the vicinity of transcription start sites in yeast, have provided
a unique insight into the cis- regulatory code of a eukaryotic genome (Venters
et al., Mol. Cell 41, 480 (2011)). Here, we show that nonspecific transcription
factor (TF)-DNA binding significantly influences binding preferences of the
majority of transcription regulators in promoter regions of the yeast genome.
We show that promoters of SAGA-dominated and TFIID-dominated genes can be
statistically distinguished based on the landscape of nonspecific protein-DNA
binding free energy. In particular, we predict that promoters of SAGA-dominated
genes possess wider regions of reduced free energy compared to promoters of
TFIID-dominated genes. We also show that specific and nonspecific TF-DNA
binding are functionally linked and cooperatively influence gene expression in
yeast. Our results suggest that nonspecific TF-DNA binding is intrinsically
encoded into the yeast genome, and it may play a more important role in
transcriptional regulation than previously thought
Hydration interactions: aqueous solvent effects in electric double layers
A model for ionic solutions with an attractive short-range pair interaction
between the ions is presented. The short-range interaction is accounted for by
adding a quadratic non-local term to the Poisson-Boltzmann free energy. The
model is used to study solvent effects in a planar electric double layer. The
counter-ion density is found to increase near the charged surface, as compared
with the Poisson-Boltzmann theory, and to decrease at larger distances. The ion
density profile is studied analytically in the case where the ion distribution
near the plate is dominated only by counter-ions. Further away from the plate
the density distribution can be described using a Poisson-Boltzmann theory with
an effective surface charge that is smaller than the actual one.Comment: 11 Figures in 13 files + LaTex file. 20 pages. Accepted to Phys. Rev.
E. Corrected typos and reference
Genome-Wide Organization of Eukaryotic Pre-Initiation Complex is Influenced by Non-Consensus Protein-DNA Binding
Energy Fluctuations Shape Free Energy of Nonspecific Biomolecular Interactions
Understanding design principles of biomolecular recognition is a key question of molecular biology. Yet the enormous complexity and diversity of biological molecules hamper the efforts to gain a predictive ability for the free energy of protein-protein, protein-DNA, and protein-RNA binding. Here, using a variant of the Derrida model, we predict that for a large class of biomolecular interactions, it is possible to accurately estimate the relative free energy of binding based on the fluctuation properties of their energy spectra, even if a finite number of the energy levels is known. We show that the free energy of the system possessing a wider binding energy spectrum is almost surely lower compared with the system possessing a narrower energy spectrum. Our predictions imply that low-affinity binding scores, usually wasted in protein-protein and protein-DNA docking algorithms, can be efficiently utilized to compute the free energy. Using the results of Rosetta docking simulations of protein-protein interactions from Andre et al. (Proc. Natl. Acad. Sci. USA 105: 16148, 2008), we demonstrate the power of our predictions