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Plasticity and Functional Modulation of Intrinsically Disordered Proteins

Abstract

A large fraction of the proteome of various organisms corresponds to polypeptides that do not form a defined three-dimensional structure. An entirely disordered polypeptide is known as an intrinsically disordered protein (IDP), and a segment of a protein that devoids a stable three-dimensional structure is called an intrinsically disordered region (IDR). It is increasingly recognized that IDRs are not simply passive disordered segments that connect well-folded domains, but they display biological functions themselves such as molecular recognition or entropic chains. IDPs and IDRs participate in a wide range of relevant cellular processes such as signal transduction pathways, RNA metabolism, and DNA packaging. However, the lack of a well-defined native structure leads to significant conceptual and methodological challenges in characterizing the structure or structural ensemble of IDPs and IDRs. Disordered proteins populate a diverse set of conformations with exceptional spatio-temporal heterogeneity and extraordinary conformational flexibility. For this reason, the elucidation of the functional mechanisms of IDPs and IDRs presupposes a full description of their structural dynamics. In this context, we propose to dissect the energy landscape of a series of biologically relevant IDPs and IDRs through an iterative approach that combines novel computational algorithms and established experimental techniques such as in-solution Small-angle X-ray scattering (SAXS), synchrotron radiation circular dichroism (SRCD) and heteronuclear multidimensional Nuclear Magnetic Resonance (NMR) spectroscopy. The computational component of this proposal relies on two methods (and associated open-source codes) developed by our groups. The Energy Landscape Visualization Method (ELViM) was conceived as a multidimensional scaling method for describing protein-folding ensembles with great potential for investigating molecular mechanisms. Because the method does not depend on reaction coordinates or native reference structures, it is well-suited to tackle IDPs and IDRs. In contrast, the Surface Assessment Via grid Evaluation (SuAVE) method accounts for the effect of curvature in the calculations of structural properties of chemical interfaces regardless of the chemical composition, symmetry, and level of atom coarseness. The proposed research will contribute to better describe the structural ensemble of molecules that do not have a stable well-characterized structure and that display broad conformational distributions. By doing so, the joint research group will work to decipher how protein plasticity modulates function, thus allowing us to infer key factors that trigger diseases such as Parkinson and diabetes Melittus, among others. The project will also contribute to the training of skilled individuals in the areas of computational biophysics and integrated structural biology, with emphasis on NMR, SRCD and SAXS. (AU)

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