New Simulation Methods at Multi-Scales and -Resolutions

描述（由申请人提供）：通常在非常大的范围内，构象运动在生物分子的功能中起着至关重要的作用，特别是在超分子复合物中。为了理解这些运动，计算机模拟在揭示结构-功能关系中涉及的能量学和动力学方面发挥了重要作用。传统的模拟方法必须依赖于精确的原子坐标知识。然而，随着结构生物学领域的进步，越来越多的情况下，人们只能获得低分辨率的分子图像，例如用冷冻电子显微镜（cryo-EM）测量的超分子复合物的图像。在这种情况下，一个人对结构的了解并不比低分辨率电子密度图所描绘的分子的粗略轮廓多多少。因此，一个挑战是开发特定的计算方法来描述运动，至少是它们的大致特征，仅仅基于分子的大致轮廓。本提案的重点是继续发展一种新的计算方法，量化弹性变形模型（QEDM），它能够仅基于电子密度图真实地模拟运动，而不需要序列和原子坐标的知识。我们的初步研究表明，QEDM可以在很宽的分辨率范围内稳健地描述运动，甚至低至20埃。更重要的是，计算揭示的构象已被证明是有用的重新分类图像的颗粒异质构象测量的低温电镜。此外，本提案旨在将QEDM应用于三种只有冷冻电镜电子密度图可用的超分子配合物，并且它们的功能涉及显着的构象灵活性。qedm辅助精化作为单粒子低温电镜技术数据处理的关键步骤，有望在低温电镜结构测定方面取得重大进展。

DESCRIPTION (provided by applicant): Conformation motions, often on a very large scale, play a vital role in the functions of biomolecules, especially in the supermolecular complexes. To understand those motions, computer simulations have played an essential role in revealing the energetics and dynamics involved in the structure-function relationship. Traditionally, all the simulation methods must rely on the knowledge of accurate atomic coordinates. However, as the field of structural biology advances, there are an increasing number of cases in which one can only obtain low-resolution images of molecules, such as those of supermolecular complexes measured by cryo-electron microscopy (cryo-EM). In those cases, one's knowledge of structures is not much more than the rough outlines of molecules delineated by low-resolution electron density maps. Therefore, a challenge is to develop specific computational methods to describe the motions, at least the gross features of them, solely based on the rough outlines of molecules. The focus of this proposal is on the continuing development of a new computational method, quantized elastic deformational model (QEDM), that is capable of realistically modeling the motions solely based on electron density maps, without the knowledge of sequence and atomic coordinates. Our preliminary studies showed that QEDM can robustly describe motions in a wide range of resolutions, even as low as 20Angstroms. More importantly, the computationally revealed conformers have been demonstrated to be useful in re-classifying images of particles with heterogeneous conformations measured by cryo-EM. In addition, this proposal aims at applying QEDM to three supermolecular complexes which have only cryo-EM electron density maps available and significant conformational flexibility has been implicated in their functions. In collaboration with cryo-EM groups, it is expected that QEDM-assisted refinement, as a key step in the data processing of single particle cryo-EM technique, will bring a major advance in cryo-EM structure determination.