Information Fusion in Biomolecular Structure and Motion Determination

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DESCRIPTION (provided by applicant): Due to their inherently complex nature, the architecture and motions of large macromolecular assemblies composed of rigid constituents are typically dissected using multiple techniques. While often combined on a case-by-case basis, the lack of theoretical tools to optimally integrate information from different sources is a major barrier to generating a more complete/accurate understanding of important assemblies. Herein are proposed new information fusion algorithms for these assemblies, and their associated functional motions. This extends classical information science to the case of data on the Lie group of rigid-body motions. Utilizing data from electron microscopy (EM) and small-angle X-ray scattering (SAXS) measurements, these fusion algorithms will be applied to two large biomolecular assemblies: (1) the ionotropic glutamate receptor (iGluR), and (2) the Chd1-nucleosome complex. The specific aims are as follows: SA1: To develop new information-theoretic methods based on Euclidean-group calculus and probability theory to improve fitting of macromolecular structures into EM densities and SAXS envelopes, and to perform information fusion of compatible biophysical information from different modalities to produce greater understanding than when methods are taken individually. SA2: To apply mathematically optimized models of iGluR quaternary structure to uncover physiologically relevant conformational changes inaccessible to individual experimental methods. SA3: To develop and apply new mathematical models of flexibility and ensemble dynamics of the nucleosome alone and in complex with the Chd1 chromatin remodeler using EM and SAXS, leading to a better understanding of the structure-motion-function relationship. The results will validate novel algorithms for fusing information from different experimental approaches to determine conformational changes in macromolecular complexes. If successful, these algorithms will provide new mechanistic insights into the iGluR family of ligand-gated ion channels, implicated in stroke and Alzheimer's disease, and the Chd1 remodeler, which has been linked to several types of cancer.