A residue level visualization of protein structures changing with time through associated water in transmembrane (TM) helices, proton channels, fast folding proteins, reverse transcriptase inhibitors and fibrils will be obtained by two dimensional infrared spectroscopy (2D IR) a powerful new method. Membrane proteins are vital to cell physiology: they include cell-surface receptors, ion channels, transporters and redox proteins. Integral membrane proteins mediate bidirectional communication between cells and the extra cellular matrix, compose one-quarter of all coding sequences in higher organisms, and more than half of all commercial drugs target them. Though essential to understanding human health, knowledge of their 3D structures and their dynamics is limited. The 2D IR with dual IR frequencies, will measure spatial correlations in the fluctuations in TM helices. Isotopic labeling of peptides and proteins and nitrile probes will enhance the spatial resolution of 2D IR and extend it to larger biological assemblies. Weak hydrogen bonds at the interfaces of TM sections of Gp A will be examined to show the bond motions and how they stabilize helix dimers. 2D IR exposes spatial arrangements across the membrane, hydrophobic effects, polarity, hydrogen bonding and other weak interactions between buried residues that enlighten the mechanisms and structural basis of helix association. The research seeks a molecular level description of key fast processes in biological assemblies from a chemical bond scale dynamics knowledge pertaining to viral infections and their therapy, cellular signaling and ion mobilization. Water stabilizes and optimizes the dynamics and functionality of living systems and a molecular level description of the dynamics of water interacting with proteins and peptides is key to understanding many cellular processes The microscopic action of a prototype M2 proton channel from Influenza A virus and how its mutants can escape inhibition, will be determined by 2D IR thereby contributing to the design of inhibitors targeting drug-resistant forms of M2. The reverse transcriptase research will acquire molecular level knowledge of HIV enzyme-inhibitor complexes. Amyloid fibrils accumulate as plaques in the brain tissue of Alzheimer's patients and our 2D IR experiments concern key water channels in these fibrils from the 40-residue peptide A?40.

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The work provides a bond scale knowledge of influenza viral infections and therapy, protein assembly and signal transduction, cell-surface receptors and ion channels. A molecular level knowledge of enzyme-inhibitors for HIV treatments and amyloid fibrils associated with Alzheimer's disease form another focus of this work.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function B Study Section (MSFB)
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Smith, Ward
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University of Pennsylvania
Schools of Arts and Sciences
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Ma, Jianqiang; Pazos, Ileana M; Gai, Feng (2014) Microscopic insights into the protein-stabilizing effect of trimethylamine N-oxide (TMAO). Proc Natl Acad Sci U S A 111:8476-81
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