Most biological activities result from a complex interplay of physiochemical interactions (electrostatics, van der Waals forces, hydrogen bonding, hydrodynamics, diffusion, and conformational transitions) that cover a broad range of length and time scales and present a significant challenge to modeling. A powerful approach to understanding such biological phenomena is through multiscale modeling methods that integrate hierarchical interactions in a self-consistent manner in combination with efficient thermodynamic sampling algorithms. In this poster, I will present the development and application of such an approach to elucidate the function of certain proteins in regulating genomic organization and gene expression; and my proposed research plans as a junior faculty.

Eukaryotic DNA is hierarchically packaged inside the nucleus. First, DNA is wrapped around protein spools called nucleosomes composed of core histone proteins. The bulk of each histone chain is involved in forming the nucleosome core while its termini, the histone tail, projects outward. This nucleoprotein complex compacts further at physiological salt conditions and, in the presence of the another histone protein, the linker histone, forms the compact 30-nm chromatin fiber. Thereafter, the chromatin fiber undergoes additional levels of folding culminating in the highly condensed chromosomes. Understanding the role of histone tails and linker histones in chromatin compaction and how the tails' posttranslatonal chemical modification modulates chromatin structure is crucial to understanding gene expression regulation and origin of genetic diseases like cancer. Recently, I have developed a new mesoscopic model of chromatin (see figure below) that correctly accounts for the salt-mediated electrostatics of the chromatin components; nucleosome core rigidity; DNA bending and supercoiling; histone tail configurational properties; and linker histone globular and C-terminal domain structures and binding orientation [1]. I have also developed the end-transfer configurational bias Monte Carlo algorithm [2] that, in combination with other local Monte Carlo "moves", allows me to efficiently sample the entire ensemble of oligonucleosome (chromatin) configurations at physiological conditions. The model has been very succesful in providing new insights into the role histone tails [3] in chromatin folding and elucidating the physical mechanism of linker-histone induced compaction of chromatin [4].

As a junior faculty, I propose to address research problems of biomedical relevance that include chromatin structure and gene regulation; RNA structure and function; and protein-DNA recognition through the development and application of molecular modeling, simulation, and theoretical methods.

[1] G. Arya, Q. Zhang, and T. Schlick, "Flexible histone tails in a new mesoscopic model of oligonucleosomes," Biophys. J. 91, 133 (2006)

[2] G. Arya and T. Schlick, "Global biopolymer sampling by end-transfer configurational-bias Monte Carlo," J. Chem. Phys., submitted (2006)

[3] G. Arya and T. Schlick, "Role of histone tails in chromatin folding revealed by a mesoscopic oligonucleosome model," Proc. Natl. Acad. Sci. USA, 103, 16236 (2006)

[4] G. Arya and T. Schlick, "Linker histones critically modulate internucleosomal pattern in chromatin," Nature, to be submitted (2006)