DECIPHERING HISTONE CODE BY COMPUTER SIMULATIONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在真核细胞中，组蛋白负责将DNA包装成致密的形式。它们的动态行为直接影响与DNA相关的所有过程，包括基因转录。事实上，组蛋白尾部的化学修饰和相关变化现在被称为“组蛋白密码”。这项拟议的工作旨在促进了解化学修饰对组蛋白尾部结构的影响。尽管具有深远的意义，但组蛋白尾巴在X射线结构中被发现是无序的。因此，它们的结构偏好及其由于化学修饰而发生的变化是未知的。我们将使用所谓的“局部增强采样”技术进行分子动力学模拟。在过去，由于系统规模和获得有意义的信息所需的模拟时间，这样的模拟被认为具有太大的挑战性。幸运的是，有了新的Cray XT3超级计算机和Amber等高效模拟程序包的开发，我们现在可以计划对组蛋白尾巴的动力学进行广泛的模拟研究。因此，我们现在申请在XT3平台上进行支持，对我们研究的可行性和方案的扩展进行初步测试。该项目的最终计划要求对组蛋白-DNA复合体进行多次模拟，并在尾部进行各种化学修饰的组合。这些包括磷酸化、甲基化、乙酰化、泛量化。在这一探索阶段的范围内，我们计划只模拟溶液中的野生型组蛋白-DNA复合体。我们的估计是，基于AMD皓龙处理器的PC集群，10,000个SU的分配可能允许我们模拟高达5.0 ns，这将足以使用“局部增强采样”技术来探索尾巴的动态行为。

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.