The proposed work is concerned with exploring how some new ideas from condensed matter physics, the theory of spin glasses, may be used to illuminate our understanding of protein folding. Spin glasses are substances which have many disordered states. Folding is the last step in the process of uncoding genetic information into functional molecules. The understanding of folding could allow more rapid advances in genetic engineering. Defects of folding may be involved in some human diseases. The new ideas have to do with trying to use spin glass theory to understand the role of intermediates and misfolded structures in the folding process and how to avoid them in computer algorithms for predicting protein structure from sequence. Several analytical studies of the thermodynamics and dynamics of spin glass models of protein folding are proposed. Computer simulations are also planned that will use the analytical information to optimize folding algorithms.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular and Cellular Biophysics Study Section (BBCA)
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University of Illinois Urbana-Champaign
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Ferreiro, Diego U; Komives, Elizabeth A; Wolynes, Peter G (2018) Frustration, function and folding. Curr Opin Struct Biol 48:68-73
Chen, Mingchen; Schafer, Nicholas P; Zheng, Weihua et al. (2018) The Associative Memory, Water Mediated, Structure and Energy Model (AWSEM)-Amylometer: Predicting Amyloid Propensity and Fibril Topology Using an Optimized Folding Landscape Model. ACS Chem Neurosci 9:1027-1039
Lu, Wei; Schafer, Nicholas P; Wolynes, Peter G (2018) Energy landscape underlying spontaneous insertion and folding of an alpha-helical transmembrane protein into a bilayer. Nat Commun 9:4949
Chen, Mingchen; Lin, Xingcheng; Lu, Wei et al. (2017) Protein Folding and Structure Prediction from the Ground Up II: AAWSEM for ?/? Proteins. J Phys Chem B 121:3473-3482
Zheng, Weihua; Tsai, Min-Yeh; Wolynes, Peter G (2017) Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1-42) and Amyloid Beta(1-40). J Am Chem Soc 139:16666-16676
Sirovetz, Brian J; Schafer, Nicholas P; Wolynes, Peter G (2017) Protein structure prediction: making AWSEM AWSEM-ER by adding evolutionary restraints. Proteins 85:2127-2142
Chen, Mingchen; Wolynes, Peter G (2017) Aggregation landscapes of Huntingtin exon 1 protein fragments and the critical repeat length for the onset of Huntington's disease. Proc Natl Acad Sci U S A 114:4406-4411
Tsai, Min-Yeh; Zhang, Bin; Zheng, Weihua et al. (2016) Molecular Mechanism of Facilitated Dissociation of Fis Protein from DNA. J Am Chem Soc :
Chen, Mingchen; Zheng, Weihua; Wolynes, Peter G (2016) Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory. Proc Natl Acad Sci U S A 113:5006-11
Chen, Mingchen; Tsai, MinYeh; Zheng, Weihua et al. (2016) The Aggregation Free Energy Landscapes of Polyglutamine Repeats. J Am Chem Soc 138:15197-15203

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