New Simulation Methods at Multi-Scales and -Resolutions

描述（由申请人提供）：构象运动，通常在非常大的尺度上，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。传统上，所有的模拟方法必须依赖于精确的原子坐标的知识。然而，随着结构生物学领域的发展，越来越多的情况下，人们只能获得低分辨率的分子图像，如超分子复合物的低温电子显微镜（cryo-EM）测量。在这些情况下，人们对结构的了解只不过是由低分辨率电子密度图描绘出的分子的粗略轮廓。因此，一个挑战是开发特定的计算方法来描述运动，至少是它们的总体特征，仅仅基于分子的粗略轮廓。这项建议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），这是能够逼真地模拟运动的电子密度图的基础上，没有序列和原子坐标的知识。我们的初步研究表明，QEDM可以鲁棒地描述运动在很宽的分辨率范围内，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，在重新分类的图像的颗粒与通过冷冻EM测量的异构构象。此外，该建议旨在将QEDM应用于三种超分子复合物，这些超分子复合物仅具有cryo-EM电子密度图，并且它们的功能中具有显着的构象灵活性。在与cryo-EM小组的合作中，预期QEDM辅助细化作为单粒子cryo-EM技术数据处理的关键步骤，将在cryo-EM结构确定方面带来重大进展。

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.