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Sequence Dependence of Transcription Factor-Mediated DNA Looping
DNA is subject to large deformations in a wide range of biological processes.
Two key examples illustrate how such deformations influence the readout of the
genetic information: the sequestering of eukaryotic genes by nucleosomes, and
DNA looping in transcriptional regulation in both prokaryotes and eukaryotes.
These kinds of regulatory problems are now becoming amenable to systematic
quantitative dissection with a powerful dialogue between theory and experiment.
Here we use a single-molecule experiment in conjunction with a statistical
mechanical model to test quantitative predictions for the behavior of DNA
looping at short length scales, and to determine how DNA sequence affects
looping at these lengths. We calculate and measure how such looping depends
upon four key biological parameters: the strength of the transcription factor
binding sites, the concentration of the transcription factor, and the length
and sequence of the DNA loop. Our studies lead to the surprising insight that
sequences that are thought to be especially favorable for nucleosome formation
because of high flexibility lead to no systematically detectable effect of
sequence on looping, and begin to provide a picture of the distinctions between
the short length scale mechanics of nucleosome formation and looping.Comment: Nucleic Acids Research (2012); Published version available at
http://nar.oxfordjournals.org/cgi/content/abstract/gks473?
ijkey=6m5pPVJgsmNmbof&keytype=re
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Investigating the cyclization of enediyne analogs using density functional theory
Enediynes are organic molecules that readily undergo a thermal rearrangement, now commonly known as the Bergman cyclization, to a cyclic para diradical form. Interest in this rearrangement was renewed when it was found to be crucial to the mechanism of cytotoxicity in a variety of natural products containing the enediyne structural moiety. Cyclization of these molecules leads to DNA strand scission and ultimately cell death. Recent efforts by medicinal chemists to discover therapeutically relevant enediyne derivatives have been complemented by computational approaches, which seek to compute energies and energetic barriers to cyclization that can accurately predict the behavior of these molecules in vivo. Here we demonstrate this approach for cis-hex-3-ene-1,5-diyne and two of its analogs using density functional theory, discuss the validity of its predictions, and investigate the effect of basis set on the description of these molecules’ reactivity.Pharmac
Capturing the essence of folding and functions of biomolecules using Coarse-Grained Models
The distances over which biological molecules and their complexes can
function range from a few nanometres, in the case of folded structures, to
millimetres, for example during chromosome organization. Describing phenomena
that cover such diverse length, and also time scales, requires models that
capture the underlying physics for the particular length scale of interest.
Theoretical ideas, in particular, concepts from polymer physics, have guided
the development of coarse-grained models to study folding of DNA, RNA, and
proteins. More recently, such models and their variants have been applied to
the functions of biological nanomachines. Simulations using coarse-grained
models are now poised to address a wide range of problems in biology.Comment: 37 pages, 8 figure
Effects of Sequence Disorder on DNA Looping and Cyclization
Effects of sequence disorder on looping and cyclization of the
double-stranded DNA are studied theoretically. Both random intrinsic curvature
and inhomogeneous bending rigidity are found to result in a remarkably wide
distribution of cyclization probabilities. For short DNA segments, the range of
the distribution reaches several orders of magnitude for even completely random
sequences. The ensemble averaged values of the cyclization probability are also
calculated, and the connection to the recent experiments is discussed.Comment: 8 pages, 4 figures, LaTeX; accepted to Physical Review E; v2: a
substantially revised version; v3: references added, conclusions expanded,
minor editorial corrections to the text; v4: a substantially revised and
expanded version (total number of pages doubled); v5: new Figure 4, captions
expanded, minor editorial improvements to the tex
J-factors of short DNA molecules
The propensity of short DNA sequences to convert to the circular form is
studied by a mesoscopic Hamiltonian method which incorporates both the bending
of the molecule axis and the intrinsic twist of the DNA strands. The base pair
fluctuations with respect to the helix diameter are treated as path
trajectories in the imaginary time path integral formalism. The partition
function for the sub-ensemble of closed molecules is computed by imposing chain
ends boundary conditions both on the radial fluctuations and on the angular
degrees of freedom. The cyclization probability, the J-factor, proves to be
highly sensitive to the stacking potential, mostly to its nonlinear parameters.
We find that the J-factor generally decreases by reducing the sequence length (
N ) and, more significantly, below N = 100 base pairs. However, even for very
small molecules, the J-factors remain sizeable in line with recent experimental
indications. Large bending angles between adjacent base pairs and anharmonic
stacking appear as the causes of the helix flexibility at short length scales.Comment: The Journal of Chemical Physics - May 2016 ; 9 page
Microscopic mechanism for experimentally observed anomalous elasticity of DNA in 2D
By exploring a recent model [Palmeri, J., M. Manghi, and N. Destainville.
2007. Phys. Rev. Lett. 99:088103] where DNA bending elasticity, described by
the wormlike chain model, is coupled to base-pair denaturation, we demonstrate
that small denaturation bubbles lead to anomalies in the flexibility of DNA at
the nanometric scale, when confined in two dimensions (2D), as reported in
atomic force microscopy (AFM) experiments [Wiggins, P. A., et al. 2006. Nature
Nanotech. 1:137-141]. Our model yields very good fits to experimental data and
quantitative predictions that can be tested experimentally. Although such
anomalies exist when DNA fluctuates freely in three dimensions (3D), they are
too weak to be detected. Interactions between bases in the helical
double-stranded DNA are modified by electrostatic adsorption on a 2D substrate,
which facilitates local denaturation. This work reconciles the apparent
discrepancy between observed 2D and 3D DNA elastic properties and points out
that conclusions about the 3D properties of DNA (and its companion proteins and
enzymes) do not directly follow from 2D experiments by AFM.Comment: To appear in Biophys. J. 8 pages, supplementary information included
(7 pages
Biological Consequences of Tightly Bent DNA: The Other Life of a Macromolecular Celebrity
The mechanical properties of DNA play a critical role in many biological
functions. For example, DNA packing in viruses involves confining the viral
genome in a volume (the viral capsid) with dimensions that are comparable to
the DNA persistence length. Similarly, eukaryotic DNA is packed in DNA-protein
complexes (nucleosomes) in which DNA is tightly bent around protein spools. DNA
is also tightly bent by many proteins that regulate transcription, resulting in
a variation in gene expression that is amenable to quantitative analysis. In
these cases, DNA loops are formed with lengths that are comparable to or
smaller than the DNA persistence length. The aim of this review is to describe
the physical forces associated with tightly bent DNA in all of these settings
and to explore the biological consequences of such bending, as increasingly
accessible by single-molecule techniques.Comment: 24 pages, 9 figure
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