In plants and animals, DNA is packaged and maintained in chromatin fibers. These structures are comprised of nucleosomes, which are made up of nucleic acid molecules wrapped around proteins called histones. Chromatin remodeling factors alter the nucleosome, thereby regulating the overall structure and stability of chromatin fibers, and modulating gene expression. In this project, the effects of two major classes of chromatin remodeling factors will be addressed with state-of-the-art computer simulations. These studies will reveal the physical basis by which cells modulate the structure and dynamics of chromosomes, and how this affects the vital process of gene expression. This project will also expose students throughout the educational system to cutting-edge biophysics research. Introductory and advanced courses will be developed that transcend traditional scientific boundaries and undergraduate and pre-and post-doctoral students will receive hands-on training. This project will increase participation in research for students from underrepresented groups, educate future middle and high school teachers, and provide training to the next generation of scientists.
Eukaryotes package and maintain their genetic code in chromatin fibers. The fundamental unit of these structures is the nucleosome, a complex of eight histone proteins that wrap ~147 base pairs of DNA. By altering the biochemical properties of the nucleosome, the cell regulates the structure and stability of chromatin and thus influences gene expression. Two of the primary mechanisms by which this occurs are post-translational modifications of histone residues and replacement of canonical histones with histone variants. The effects of these chromatin remodeling factors on the structures and stabilities of nucleosomes have been extensively studied. However, it is only in recent years that it has become evident that chromatin exhibits significant conformational dynamics, the details of which, and how remodeling factors influences them, remain elusive. The goal of this project is to determine how post-translational modifications and histone variants affect intra- and inter-nucleosome dynamics as a means of regulating gene expression. This project will test the hypothesis that chromatin remodeling factors function by creating local perturbations that propagate through allosteric networks to induce global changes in nucleosomes and chromatin fibers. To do this, biomolecular simulations will be performed to address (1) how the local effects of post-translational modifications at dynamic hotspots influence global structures and dynamics, and (2) how the effects of histone variants propagate through inter-nucleosomal dynamical networks into chromatin fibers. This will be done with all-atom and coarse-grain molecular dynamics simulations, and will utilize conventional, enhanced sampling, and free energy methods. This work will be performed in close collaboration with experimentalists working in the fields of nuclear magnetic resonance spectroscopy and small angle X-ray scattering, whose results will help inform, validate, and guide the development of future simulations. This project will significantly expand emerging paradigm that nucleosome functions are closely related to their conformational dynamics and provide insights into the mechanism by which nature modulates multicomponent protein/DNA systems.
