New Simulation Methods at Multi-Scales and -Resolutions

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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.