New Simulation Methods at Multi-Scales and -Resolutions

描述(申请人提供)：构象运动，通常是非常大的规模，在生物分子的功能中扮演着重要的角色，特别是在超分子复合体中。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至关重要的作用。传统上，所有的模拟方法都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发展，人们只能获得分子的低分辨率图像的情况越来越多，例如用冷冻电子显微镜(Cryo-EM)测量的超分子复合体的图像。在这些情况下，一个人对结构的了解仅仅是低分辨率电子密度图描绘的分子的粗略轮廓。因此，一个挑战是开发专门的计算方法来描述运动，至少描述它们的总体特征，仅仅基于分子的粗略轮廓。这项提议的重点是继续开发一种新的计算方法--量化弹性变形模型(QEDM)，该模型能够仅基于电子密度图对运动进行现实建模，而不需要知道序列和原子坐标。我们的初步研究表明，QEDM可以很好地描述各种分辨率的运动，甚至可以低至20埃。更重要的是，通过计算揭示的构象已经被证明在重新分类具有冷冻-EM测量的非均相构象的粒子图像中是有用的。此外，这项建议旨在将QEDM应用于三个只有冷冻-EM电子密度图的超分子络合物，并且它们的功能涉及显著的构象柔性。通过与CRYO-EM小组的合作，预计QEDM辅助细化作为单粒子CRYO-EM技术数据处理的关键步骤，将在低温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.