The Ultrafast Laser Resource at the University of Pennsylvania is founding the technoogies for multidimensional infrared spectroscopy in biological and biomedical research including drug design. The components of the laboratory are an integrated multifaceted attack on advancing two dimensional infrared methods. Each TR&D is dynamically evolving at the cutting edge of infrared technology, they are mutually supportive. The utility of 2D IR in biomedical applications is increasing substantially. Just within the last year a protein structure has been determined by 2D IR. TR&D's #1 focuses on phototriggered states, the technology combines optical and infrared methods to obtain 2D IR structural-time dependent information during nonequilibrium dynamical processes. The TR&D #2 concerns dual frequency 2D IR which combines into a two dimensional spectrum the excitation of two modes having widely separated frequencies of proteins and proton channels. TR&D#3 involves a specialization on structure determination, to build on previous studies using 2D IR, by improvements in the methodology that are specifically geared towards the equilibrium dynamics of structures of proteins on time scales that have not been achieved by other structural methods. Six DBF's are included: (1)The M2 proton channel of the Influenza A virus: properties of channel water (W.F. DeGrado, UCSF).(2)The structure and dynamics of amyloid A40 fibrils and their formation kinetics (P. Abelson, Upend) (3) Phototriggering of conformational change (A.B. Smith, Upend)) (4) Pushing the Structural Resolution Limit of Linear and Nonlinear Infrared Spectroscopies (F. Gai, Upend) (5) Radical pair dynamics by optically triggered - IR probe spectroscopy (S. Vinogradov, Upend) (6) Spectroscopy and dynamics of HlV-1 RT/inhibitor complexes probed by 2D IR methods and MD simulations (E. Arnold, Rutgers). The proposal also includes seven Collaborative and Service projects on (1) Nitrile and Azide probes (Brewer) (2) Protonated histidines (Londergan) (3) Amyloid fluorescence (Petersson)(4) Blood coagulation (Knshnaswamy) (5) Kinases models (Sarkar)(6)Amyloid kinetics (Dai) (7) Oxygen microscopy (Vinogradov), The Resource provides training for users, and the work is widely disseminated.

Public Health Relevance

The resource employs driving biomedical projects, collaborative and service projects to explore and advance new methods of structure determination with ultrafast infared pulses which are applied in these research projects to expose mechanisms of action of the influenza A virus and HIV AIDS drugs acting on reverse transcriptase, the folding and misfolding of amyloid proteins and of dysregulaed blood coagulation

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Biotechnology Resource Grants (P41)
Project #
9P41GM104605-31
Application #
8339970
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (40))
Program Officer
Friedman, Fred K
Project Start
1997-08-01
Project End
2017-05-31
Budget Start
2012-08-16
Budget End
2013-05-31
Support Year
31
Fiscal Year
2012
Total Cost
$1,096,627
Indirect Cost
$364,092
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Markiewicz, Beatrice N; Lemmin, Thomas; Zhang, Wenkai et al. (2016) Infrared and fluorescence assessment of the hydration status of the tryptophan gate in the influenza A M2 proton channel. Phys Chem Chem Phys 18:28939-28950
Zhang, Wenkai; Markiewicz, Beatrice N; Doerksen, Rosalie S et al. (2016) C≡N stretching vibration of 5-cyanotryptophan as an infrared probe of protein local environment: what determines its frequency? Phys Chem Chem Phys 18:7027-34
Rodgers, Jeffrey M; Zhang, Wenkai; Bazewicz, Christopher G et al. (2016) Kinetic Isotope Effect Provides Insight into the Vibrational Relaxation Mechanism of Aromatic Molecules: Application to Cyano-phenylalanine. J Phys Chem Lett 7:1281-7
Eisenberg, Azaria S; Nathan, Moshe; Juszczak, Laura J (2016) Excited State Electron Distribution and Role of the Terminal Amine in Acidic and Basic Tryptophan Dipeptide Fluorescence. J Mol Struct 1118:56-67
Abaskharon, Rachel M; Gai, Feng (2016) Meandering Down the Energy Landscape of Protein Folding: Are We There Yet? Biophys J 110:1924-32
Ding, Bei; Hilaire, Mary Rose; Gai, Feng (2016) Infrared and Fluorescence Assessment of Protein Dynamics: From Folding to Function. J Phys Chem B 120:5103-13
Abaskharon, Rachel M; Gai, Feng (2016) Direct measurement of the tryptophan-mediated photocleavage kinetics of a protein disulfide bond. Phys Chem Chem Phys 18:9602-7
Markiewicz, Beatrice N; Mukherjee, Debopreeti; Troxler, Thomas et al. (2016) Utility of 5-Cyanotryptophan Fluorescence as a Sensitive Probe of Protein Hydration. J Phys Chem B 120:936-44
Oh, Kwang-Im; Fiorin, Giacomo; Gai, Feng (2015) How Sensitive is the Amide I Vibration of the Polypeptide Backbone to Electric Fields? Chemphyschem 16:3595-8
Abaskharon, Rachel M; Culik, Robert M; Woolley, G Andrew et al. (2015) Tuning the Attempt Frequency of Protein Folding Dynamics via Transition-State Rigidification: Application to Trp-Cage. J Phys Chem Lett 6:521-6

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