Rice University scientists
simulated a nucleosome coiled in DNA to discover the interactions that
control its unwinding. The DNA double helix binds tightly to proteins
(in red, blue, orange and green) that make up the histone core, which
exerts control over the exposure (center and right) of genes for
binding.
Credit: Wolynes Lab/Rice University
The protein complex that holds strands
of DNA in compact spools partially disassembles itself to help genes
reveal themselves to specialized proteins and enzymes for activation,
according to Rice University researchers and their colleagues.
The team's detailed computer models support the idea that DNA
unwrapping and core protein unfolding are coupled, and that DNA
unwrapping can happen asymmetrically to expose specific genes.
The study of nucleosome disassembly by Rice theoretical biological
physicist Peter Wolynes, former Rice postdoctoral researcher Bin Zhang,
postdoctoral researcher Weihua Zheng and University of Maryland
theoretical chemist Garegin Papoian appears in the Journal of the American Chemical Society.
The research is part of a drive by Rice's Center for Theoretical
Biological Physics (CTBP) to understand the details of DNA's structure,
dynamics and function.
The spools at the center of nucleosomes, the fundamental unit of DNA
organization, are histone protein core complexes. Nucleosomes are buried
deep within a cell's nucleus. About 147 DNA base pairs (from the more
than 3 billion in the human genome) wrap around each histone core 1.7
times. The double helix moves on to spiral around the next core, and the
next, with linker sections of 20 to 90 base pairs in between.
The structure helps squeeze a 6-foot-long strand of DNA in each cell
into as compact a form as possible while facilitating the controlled
exposure of genes along the strand for protein expression.
The spools consist of two pairs of heterodimers, macromolecules that
join to form the core. The core is stable until genes along the DNA are
called upon by transcription factors or RNA polymerases; the
researchers' goal was to simulate what happens as the DNA unwinds from
the core, making itself available to bind to outside proteins or make
contact with other genes along the strand.
The researchers used their energy landscape models to simulate the
nucleosome disassembly mechanism based on the energetic properties of
its constituent DNA and proteins. The landscape maps the energies of all
the possible forms a protein can take as it folds and functions.
Conceptual insights from energy landscape theory have been implemented
in an open-source biomolecular modeling framework called AWSEM Molecular
Dynamics, which was jointly developed by the Papoian and Wolynes
groups.
Wolynes said most studies elsewhere treated the histone core as if it
were rigid and irreversibly disassociated when DNA unwrapped. But more
recent experimental studies that involved gently pulling strands of DNA
or used fluorescent resonance energy transfer, which measures energy
moving between two molecules, showed the protein core is flexible and
does not completely disassemble during unwrapping.
In their simulations, the researchers found the core changed its
shape as the DNA unwound. Without DNA, they found the histone core was
completely unstable in physiological conditions.
Their simulations showed that histone tails -- the terminal regions
of the core proteins -- play a crucial role in nucleosome stability. The
tails are highly charged and bind tightly with DNA, keeping its genomic
content from being exposed until necessary. Their models predicted a
faster unwrapping for tail-less nucleosomes, as seen in experiments.
The nucleosome study is part of a larger effort both by Papoian at
Maryland and by Wolynes with his colleagues at CTBP to understand the
mechanics of DNA, from how it functions to how it reproduces during
mitosis. Wolynes said the new study and another new one by his lab on
DNA during mitosis represent the opposite ends of the size scale.
"We can understand things at each end of the scale, but there's a
no-man's land in between," he said. "We'll have to see whether the
phenomena in the present-day no-man's land can be understood. I don't
believe in magic; I believe they eventually will."
Wolynes is the D.R. Bullard-Welch Foundation Professor of Science, a
professor of chemistry, of biochemistry and cell biology, of physics and
astronomy and of materials science and nanoengineering at Rice and a
senior investigator of the National Science Foundation (NSF)-funded
CTBP. Papoian is the Monroe Martin Professor and chemical physics
director at the University of Maryland. Zhang will join the
Massachusetts Institute of Technology as an assistant professor in July.