186. COMPUTATIONAL MODELING OF NUCLEOSOME UNRAVELING

Department: NanoEngineering
Faculty Advisor(s): Gaurav Arya

Primary Student
Name: Irina Vladinizovna Dobrovolskaia
Email: idobrovo@ucsd.edu
Phone: 858-232-3323
Grad Year: 2012

Abstract
Our DNA is packaged inside cells through the formation of a ~30-nm thick chromatin fiber composed of repeating units called nucleosomes. Each nucleosome consists of 146 bp of DNA wrapped 1.7 times around a histone octamer - a spool made of eight histone proteins. How proteins access DNA sequences buried deep within the nucleosome remains an open question, but it may be argued that any such mechanism must involve forces that unwrap the DNA off the surface of the histone octamer. To investigate the dynamics of such force-induced unwrapping of DNA, we have developed a coarsegrained model of the nucleosome The model has been parameterized to reproduce the experimentally obtained DNA/histone interaction free energy profile, derived from single-molecule unzipping of nucleosomal DNA, and the rate-dependent unwrapping forces, obtained from single-molecule pulling measurements. Brownian dynamics simulations of this model under constant loading reveal the detailed dynamics of nucleosome unraveling. Consistent with experiments, the first turn of nucleosomal DNA unwraps reversibly while the second turn wraps irreversibly, signified by a notable peak in the force-extension profile. We also uncover the details of unwrapping kinetics and the nucleosome flipping motions that often accompany the unraveling. The model also reveals that the strong interactions ~35 bp from the entry/exit sites of the nucleosome are required to maintaining the stability of the nucleosome against pulling forces while allowing for dynamic accessibility of DNA sequences near the entry/exit site.

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