SIMULATIONS OF SUPRAMOLECULAR BIOLOGICAL STRUCTURES

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。 我们建议研究细胞内蛋白质和蛋白质复合体的组织和功能，以阐明原子尺度的动力学如何驱动大规模的细胞过程。在我们的研究中，我们使用了我们实验室开发的高效分子动力学(MD)程序NAMD，对几乎所有细胞生物中发生的七个关键过程进行了大规模和长期的模拟。MD为实验技术无法实现的这些过程的研究提供了时间和空间的同时分辨率。使用我们最近开发的MD灵活拟合方法，我们将MD和实验结合起来，获取原子分辨率但非生理的晶体结构，并将它们拟合到较低分辨率但生理相关的电子显微镜数据中，得到代表功能大分子系统的结构。事实上，我们所有的项目都涉及到与实验者的密切合作。我们建议研究(I)蛋白质如何从展开的起始序列折叠，(Ii)蛋白质是如何由核糖体合成的，以及(Iii)新生蛋白质是如何输出到细胞膜或排泄出来的。在更大的范围内，我们试图研究细胞如何通过被称为(Iv)条结构域的蛋白质或通过(V)完整的膜蛋白来形成其内膜。最后，我们研究了细胞转录的关键成分，(Vi)解开双链DNA的解旋酶，以及(Vii)控制细胞质和核质之间进出口的核孔蛋白。

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. We propose to investigate the organization and function of proteins and protein complexes within cells in order to elucidate how atomic-scale dynamics drives large-scale cellular processes. For our studies, we employ the highly efficient molecular dynamics (MD) program NAMD, developed in our lab, to carry out large-size and long-time simulations of seven key processes taking place in nearly all cellular organisms. MD affords a simultaneous resolution in both time and space for the study of these processes unattainable by experimental techniques. With our recently developed MD Flexible Fitting method, we join MD and experiment, taking atomic-resolution, but unphysiological, crystal structures and fit them to lower resolution, but physiologically relevant, electron-microscopy data, yielding structures representing functional macro-molecular systems. Actually, all of our projects involve close collaboration with experimentalists. We propose to study (i) how proteins fold from an unfolded starting sequence, (ii) how proteins are synthesized by the ribosome and (iii) how nascent proteins are exported into cellular membranes or excreted. On a larger scale, we seek to study how cells shape their internal membranes, by proteins called (iv) BAR domains or by (v) integral membrane proteins. Lastly, we investigate key components of transcription in cells, (vi) helicases, that unwind double stranded DNA, and (vii) nuclear pore proteins that control export and import between a cells cytoplasm and nucleoplasm.