Understanding protein folding from a molecular perspective is one of the central challenges in modern biophysics. Current experimental techniques only provide a relatively limited view of the ultrafast fluctuations and long-range conformational changes that biomolecules undergo in solution. The first objective of this project is to develop an experimental framework based on ultrafast multidimensional infrared spectroscopy that will measure protein structure with sub- picosecond time resolution, offering a detailed view of non-equilibrium processes such as folding, denaturation, and protein aggregation. The experimental data will be supported by cutting-edge molecular dynamics simulations, which are now possible due to recent developments in distributed computing, as well as structure-frequency maps that provide the connection between molecular structures and vibrational frequencies. Another component of the project will aim at developing a general experimental method to quantify the structure of proteins in solution from an analytical perspective with the goal of implementing methods for measuring the structure, conformational flexibility, and solvent exposure of globular proteins.

Public Health Relevance

Investigating the mechanisms of protein folding is the initial step towards determining the molecular origins of neurodegenerative disorders such as Parkinson; Huntington and Alzheimer's diseases as well as understanding protein-drug interactions from a dynamical standpoint. The goal of this project is to develop a general technique-based on a combination of ultrafast infrared spectroscopy; frequency maps; and cutting-edge molecular dynamics simulations-to extract biomolecular structure and dynamics; including protein denaturation; folding; and aggregation pathways by measuring the correlated motions between residues as the proteins undergo conformational changes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04-D (20))
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Flicker, Paula F
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University of Chicago
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Baiz, Carlos R; Tokmakoff, Andrei (2015) Structural disorder of folded proteins: isotope-edited 2D IR spectroscopy and Markov state modeling. Biophys J 108:1747-57
Stevenson, Paul; Götz, Christoph; Baiz, Carlos R et al. (2015) Visualizing KcsA conformational changes upon ion binding by infrared spectroscopy and atomistic modeling. J Phys Chem B 119:5824-31
Baiz, Carlos R; Schach, Denise; Tokmakoff, Andrei (2014) Ultrafast 2D IR microscopy. Opt Express 22:18724-35
Baiz, Carlos R; Lin, Yu-Shan; Peng, Chunte Sam et al. (2014) A molecular interpretation of 2D IR protein folding experiments with Markov state models. Biophys J 106:1359-70
Peng, Chunte Sam; Baiz, Carlos R; Tokmakoff, Andrei (2013) Direct observation of ground-state lactam-lactim tautomerization using temperature-jump transient 2D IR spectroscopy. Proc Natl Acad Sci U S A 110:9243-8