Molecular nanotechnology includes frontier research areas like
supramolecular chemistry, protein engineering, and molecular design and
modeling. In molecular modeling, much interest is focused on DNA, whose
structure and versatility spans many orders of spatial and temporal
dimensions, from the base pair level to condensed chromosomes in the cell.
Specifically, in eukaryotic organisms, chromosomal DNA is packaged in the
nucleoprotein complex called chromatin. Chromatin structure governs
fundamental genome packaging and regulatory processes, such as
transcription and replication. Yet the internal structure of the chromatin
fiber --- let alone the structural pathways for folding and unfolding ---
remains unknown despite progress on biochemical mechanisms that control
localized folding. It is known that the chromatin building block of core
proteins, termed the nucleosome, serves as the spool around which DNA is
coiled, stabilizing a net negative supercoiling. Furthermore, it is
recognized that at physiological salt conditions, nucleosomes
self-organize into compact structures (such as a condensed tightly-wound
form termed the ``30-nm fiber'') and that, at low salt, chromatin
spontaneously expands to a ``bead-on-a-string'' structure. Higher-order
forms of chromatin exist and regulate DNA accessibility, although detailed
structures are not known.
To offer structural insights into how this nucleoprotein complex might be
organized, as well as to test and refine geometric/topological models
(e.g., zigzag vs. solenoid, straight vs. bent linker DNA) for chromatin
organization, we have developed a mesoscale computer model describing the
mechanics of the chromatin fiber on the polymer level. Polynucleosomes are
represented as a series of electrostatically charged DNA beads, tethered
to, and wrapped around, charged nucleosome cores. Each nucleosome is
modeled by two linked cylinders (nucleosome core and protruding H3 tail)
with 277 surface charges, which reproduce the far-field Poisson-Boltzmann
potential with low error at a wide range of salt concentrations; the
linker DNA between nucleosomes is represented as five wormlike-chain beads
based on the average of 50 bp per linker. Millisecond Brownian dynamics
simulations reveal salt-dependent condensation/unfolding in high and low
salt respectively, reproducing the cooperative aggregation of nucleosomes
in vitro. Our 30-nm chromatin model reveals an organization of 4
nucleosomes/10~nm and bridges helical and zigzag models with gently-bent
DNA. Future studies will focus on the structural/functional consequences
of histone tails, histone variants, and biochemical modifications of
nucleosomes on chromatin organization.
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