Significance of Knotted Structures for Function of Proteins and Nucleic Acids
Friday Abstracts
Chromatin Looping and Interdigitation Mechanisms: Insights from Mesoscale Simulations
Antoni Luque,
Tamar Schlick
.
NYU, New York, USA.
In all eukaryotic organisms, the chromatin fibers, composed of DNA complexed with core
histones and linker histone proteins, store a vast amount of information. The chromatin building
blocks, namely nucleosomes -- nanometric beads made of DNA and eight core histones --
connect to one another by DNA linkers and form hierarchical structures whose folds are essential
for the nderstanding of basic regulatory processes in the cell. However, the precise organization
of chromatin remains elusive. In particular, it is not clear whether chromatin organizes in
independent or inter-digitated fibers. To address this question, we have developed and applied a
mesoscale computational model in collaboration with experiments to probe structural, energetic,
and dynamical questions associated with chromatin as a function of various internal and external
factors. We will describe several mechanisms that affect fiber architecture, including the size of
the linker DNAs and the presence of linker histones. Depending on the conditions, these
molecular mechanisms favor the formation of segregated fibers, inter-digitated fibers, and
chromatin loops. The modeling thus helps interpret the variation in chromatin fibers for different
cell types and represents a reference framework to investigate local and global mechanisms that
regulate chromatin structure in the nucleus.
Protein-induced Entanglement on DNA: Connecting and Organizing Chromosomes via
Multiple Loops.
Nicolas Clauvelin
1
, Wilma K. Olson
1,2
.
1
Rutgers University, Piscataway, NJ, USA,
2
Rutgers University, Piscataway, NJ, USA.
The control of gene expression sometimes entails the folding of DNA into looped structures
mediated by the binding of protein. Although the literature abounds with examples of single
DNA loops induced by the attachment of sequentially distant genetic elements on a common
protein core, recent studies have demonstrated the occurrence of multiple loops formed by three
or more remote, protein-anchored sites. The direct physical connections between these DNA
sites stem from the capability of protein, such as the
Escherichia coli
Gal repressor, to form
oligomeric structures. Structure-based genetic analyses have shown that dimeric units of the Gal
repressor stack one above the other in a V-shaped tetrameric assembly. Repeated dimeric
associations of the same type lead to higher-order helical protein pathways that can secure
multiple chromosomal connections. We are examining the entanglement of DNA loops that
attach to such proteins with the help of a novel energy minimization method. Our method makes
it possible to optimize DNA pathways at the base-pair level under various constraints, such as
imposed end-to-end displacement and rotation. We focus on the multiple loops that can be
induced by oligomeric Gal assemblies and compute the relevant energy landscapes and
topological properties as functions of the number of Gal repressors and the chain lengths of the
different loops. The binding of the less stacked Lac repressor to a DNA minicircle, which
segregates the double helix in two loops, is also investigated. In addition, we take advantage of
the fact that our optimization method accounts for the presence along DNA of bound ligands to
study how the binding of architectural proteins (
e.g.
, the
Escherichia coli
histone-like HU
protein) can ease or suppress the formation of such loops.
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