Protein hydration is a long-standing and unresolved problem in protein science and water-protein interactions/dynamics are essential to a protein's structure, dynamics and function. The elucidation of such coupling motions at the molecular level not only has fundamental significance in understanding protein stability and flexibility, folding, misfolding and aggregation, recognition and binding, and enzyme catalysis, but also has a significant impact on practical applications such as drug design. Various methods and strategies have been used to characterize water motions around proteins, but such studies have been challenging and difficult because the dynamics are ultrafast and heterogeneous. A general molecular picture has not been obtained yet. We have recently developed a methodology by integrating state-of-the-art femtosecond laser spectroscopy and site-directed mutagenesis and have reached femtosecond temporal resolution and single-residue spatial resolution. Using intrinsic amino acid tryptophan as a local optical probe, we have recently mapped out the global water motions around an a-helical globular protein with unprecedented details. In this proposal, we will systematically characterize water motions around small structural motifs, on surfaces of ?-sheet globular proteins, and at interfaces of protein-DNA complexes. Specifically, Aim 1 is to elucidate the hydration dynamics evolution by systematic characterization of water motions from an a-helix, to a ?-hairpin, to a small cage, and to a mini-protein. With the fundamental understanding of water motions around these elemental structure units, in Aim 2 we extend to characterize the global surface hydration dynamics around two ?-sheet globular proteins. Combined with recently characterized water dynamics around the a-helical globular protein, we hope that such systematic comparisons will reveal the different dynamic nature of water motions around different protein architectures with different size, rigidity, chemical identity. Finally, in Aim 3, we investigate the interfacial hydration dynamics by systematic characterization of water motions at the interfaces of two protein-DNA complexes to address the dynamic role of water motions in mediation of protein-DNA recognition. The new knowledge obtained from these systematic investigations is fundamental to a wide variety of biological processes and also significant to a series of practical applications.

Public Health Relevance

Water is an active matrix of life and water-protein interactions are essential to protein structure, dynamics and function. Here we develop a novel method with femtosecond temporal resolution and single-residue spatial resolution to systematically characterize water motions around protein surfaces/interfaces and thus reveal the molecular mechanism of water-protein interactions. The new knowledge from these studies is fundamental to a wide variety of biological processes such as molecular recognition and enzyme catalysis and also significant to a series of practical applications such as drug design and prevention of protein aggregation to neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM095997-04
Application #
8725688
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Smith, Ward
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Yang, Yi; Qin, Yangzhong; Ding, Qing et al. (2014) Ultrafast water dynamics at the interface of the polymerase-DNA binding complex. Biochemistry 53:5405-13