The overall objective of this proposal is to characterize the dynamics and molecular mechanisms of protein folding. We seek to determine the characteristic rates and underlying molecular mechanisms of the fundamental processes, including chain collapse, secondary structure formation, and formation of specific tertiary interactions. The basic questions we plan to address include: What are the fundamental dynamics, transition state structures and folding mechanisms of ultrafast folding proteins? Can ultrafast folding proteins be made to fold without crossing a free energy barrier (downhill folding)? What is the role of residual structure in the denatured state, and does such structure speed folding? Do peptide models and ultrafast folding subdomains exhibit the same folding behavior in the context of the full protein? These questions are the subject of intense scrutiny and debate in the current protein folding literature. We propose a close interaction between experiment and simulation to answer these questions. We have designed experimental approaches to quantitatively test the predictions of MD simulations of ultrafast folding proteins. In turn, we expect MD simulations to motivate new experiments, or help in the interpretation of experimental observables. We expect such a close interplay between experiment and theory to greatly benefit both, and ultimately improve our understanding of how proteins fold.
Understanding how a protein folds to its native, biologically active structure continues to be a central problem of modern biology, with important practical consequences for rational protein design, protein structure prediction and folding related disease states. The aggregation and deposition of misfolded proteins, sometimes the consequence of a single point mutation, is a common feature of neurodegenerative disorders as diverse as Alzheimer's disease, Parkinson's disease, prion diseases, Huntington's disease, and motor neuron disease. The proposed work will provide new understanding of how proteins fold, and what goes wrong when they misfold and cause disease. ? ? ?
|Davis, Caitlin M; Reddish, Michael J; Dyer, R Brian (2017) Dual time-resolved temperature-jump fluorescence and infrared spectroscopy for the study of fast protein dynamics. Spectrochim Acta A Mol Biomol Spectrosc 178:185-191|
|Zanetti-Polzi, Laura; Davis, Caitlin M; Gruebele, Martin et al. (2017) Parallel folding pathways of Fip35 WW domain explained by infrared spectra and their computer simulation. FEBS Lett 591:3265-3275|
|Jeong, Ban-Seok; Dyer, R Brian (2017) Proton Transport Mechanism of M2 Proton Channel Studied by Laser-Induced pH Jump. J Am Chem Soc 139:6621-6628|
|Reid, Keon A; Davis, Caitlin M; Dyer, R Brian et al. (2017) Binding, folding and insertion of a ?-hairpin peptide at a lipid bilayer surface: Influence of electrostatics and lipid tail packing. Biochim Biophys Acta 1860:792-800|
|Davis, Caitlin M; Dyer, R Brian (2016) The Role of Electrostatic Interactions in Folding of ?-Proteins. J Am Chem Soc 138:1456-64|
|Schuler, Erin E; Nagarajan, Sureshbabu; Dyer, R Brian (2016) Submillisecond Dynamics of Mastoparan X Insertion into Lipid Membranes. J Phys Chem Lett 7:3365-70|
|Davis, Caitlin M; Cooper, A Kat; Dyer, R Brian (2015) Fast helix formation in the B domain of protein A revealed by site-specific infrared probes. Biochemistry 54:1758-66|
|Kise, Drew P; Reddish, Michael J; Dyer, R Brian (2015) Sandwich-format 3D printed microfluidic mixers: a flexible platform for multi-probe analysis. J Micromech Microeng 25:|
|Kise, Drew P; Magana, Donny; Reddish, Michael J et al. (2014) Submillisecond mixing in a continuous-flow, microfluidic mixer utilizing mid-infrared hyperspectral imaging detection. Lab Chip 14:584-91|
|Davis, Caitlin M; Dyer, R Brian (2014) WW domain folding complexity revealed by infrared spectroscopy. Biochemistry 53:5476-84|
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