DECIPHERING HISTONE CODE BY COMPUTER SIMULATIONS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Histones are responsible for packaging DNA into compact forms in eukaryotic cells. Their dynamic bahevior directly influences all processes related to DNA, including gene transcription. In fact, the chemical modification and related changes of the histone tails are now referred to as "histone code". The proposed work is aimed at facilitating the understanding the influence of the chemical modification on the histone tails to their structures. Despite the profound significance, histone tails are found to be disordered in the X-ray structures. Thus, their structural preference and its changes due to chemical modification is simply unknown. We will perform molecular dynamics simulations using the so-called "locally enhanced sampling" technique. In the past, such simulations were deemed too challenging to contemplate because of the system size and the simulation time required to obtain meaningful information. Fortunately, with the new Cray XT3 supercomputer and the development of efficient simulation packages such as AMBER, we can now plan to conduct extensive simulation research on the dynamics of the histone tails. Thus, we now apply for support on the XT3 platform to conduct initial tests on the feasibility of our study and scaling of the program. The final plan of this project calls for multiple simulations of histone-DNA complex with a variety of combinations of chemical modifications on the tails. These include phosphorylation, methylation, acetylation, ubiqutination. Within the scope of this exploratory phase, we plan to simulate only the wild-type histone-DNA complex in solution. Our estimation, based on a PC cluster of AMD Opteron CPUs, is that the 10,000 SU allocation may allow us to simulate up to 5.0 ns, which would be sufficient to explore the dynamic behavior of the tails using the "locally enhanced sampling" technique.