SIMULATIONS OF SUPRAMOLECULAR BIOLOGICAL STRUCTURES

这个子项目是许多利用 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来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们建议研究细胞内蛋白质和蛋白质复合物的组织和功能，以阐明原子尺度动力学如何驱动大规模的细胞过程。在我们的研究中，我们采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时间的模拟。MD提供了一个同时解决方案，在时间和空间的研究，这些过程无法达到的实验技术。随着我们最近开发的MD灵活拟合方法，我们加入MD和实验，采取原子分辨率，但非生理，晶体结构，并将它们拟合到较低的分辨率，但生理相关的电子显微镜数据，产生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与实验者的密切合作。我们建议研究（i）蛋白质如何从未折叠的起始序列折叠，（ii）蛋白质如何由核糖体合成，以及（iii）新生蛋白质如何被输出到细胞膜或排出体外。在更大的范围内，我们试图研究细胞如何通过称为（iv）BAR结构域或（v）整合膜蛋白的蛋白质来塑造其内部膜。最后，我们研究了细胞中转录的关键成分，（六）解旋酶，解开双链DNA，和（七）核孔蛋白，控制出口和进口之间的细胞质和核质。

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.