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.

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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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function B Study Section (MSFB)
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Smith, Ward
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Ohio State University
Schools of Arts and Sciences
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Qin, Yangzhong; Wang, Lijuan; Zhong, Dongping (2016) Dynamics and mechanism of ultrafast water-protein interactions. Proc Natl Acad Sci U S A 113:8424-9
Gu, Xiaobo; Park, Sun-Young; Tonelli, Marco et al. (2016) NMR Structures and Dynamics in a Prohead RNA Loop that Binds Metal Ions. J Phys Chem Lett 7:3841-3846
Jia, Menghui; Yang, Jin; Qin, Yangzhong et al. (2015) Determination of Protein Surface Hydration by Systematic Charge Mutations. J Phys Chem Lett 6:5100-5
Liu, Zheyun; Li, Xiankun; Zhong, Frank W et al. (2014) Quenching Dynamics of Ultraviolet-Light Perception by UVR8 Photoreceptor. J Phys Chem Lett 5:69-72
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
Qin, Yangzhong; Yang, Yi; Zhang, Luyuan et al. (2013) Direct probing of solvent accessibility and mobility at the binding interface of polymerase (Dpo4)-DNA complex. J Phys Chem A 117:13926-34
Yang, Jin; Zhang, Luyuan; Wang, Lijuan et al. (2012) Femtosecond conical intersection dynamics of tryptophan in proteins and validation of slowdown of hydration layer dynamics. J Am Chem Soc 134:16460-3
Qin, Yangzhong; Chang, Chih-Wei; Wang, Lijuan et al. (2012) Validation of response function construction and probing heterogeneous protein hydration by intrinsic tryptophan. J Phys Chem B 116:13320-30