DECIPHERING HISTONE CODE BY COMPUTER SIMULATIONS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 组蛋白负责在真核细胞中将DNA包装成紧凑形式。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”。本文的工作旨在促进对组蛋白尾部的化学修饰对其结构的影响的理解。尽管意义深远，但在X射线结构中发现组蛋白尾部是无序的。因此，它们的结构偏好及其由于化学修饰而引起的变化是完全未知的。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，这种模拟被认为是太具有挑战性的考虑，因为系统的大小和获得有意义的信息所需的模拟时间。幸运的是，随着新的Cray XT 3超级计算机和AMBER等高效模拟软件包的开发，我们现在可以计划对组蛋白尾部的动力学进行广泛的模拟研究。因此，我们现在申请XT 3平台的支持，对我们的研究和项目规模的可行性进行初步测试。该项目的最终计划要求对组蛋白-DNA复合物进行多次模拟，并在尾部进行各种化学修饰组合。这些包括磷酸化、甲基化、乙酰化、泛素化。在这个探索阶段的范围内，我们计划只模拟溶液中的野生型组蛋白-DNA复合物。基于AMD Opteron CPU的PC集群，我们的估计是10，000 SU分配可以允许我们模拟高达5.0 ns，这足以使用“局部增强采样”技术来探索尾部的动态行为。

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.