Protein dynamics is essential for its biological function. With integration of molecular biology, state-of-the-art time-resolved laser spectroscopy and computation simulations, the biological dynamics now can be studied from the initial ultrafast motions to longtime fluctuations on the most fundamental level. The molecular mechanisms thus can be revealed. We have recently investigated the dynamics and mechanism of water-protein interactions and elucidated the fundamental water-protein coupling motions occurring on the picosecond time scales, an ideal timescale to bridge the gap between ultrafast bulk-water motions and slow protein fluctuations. The understanding of biological water is significant to a variety of biological activities such as protein-ligand/drug recognition and enzymatic catalysis. In another direction, we also made significant advances on repair of UV-damaged DNA and mapped out most repair processes in real time, including a series of ultrafast elementary reactions. We will elucidate the complete repair photocycles at the local molecular level over a wide time scale from femtoseconds to milliseconds and provide a molecular basis for potential applications such as rational drug design for curing skin cancer. In this new effort, we will build a novel time-resolved method to explore complex systems over a wide time range on two major areas of (1) investigating interfacial water dynamics at protein-DNA and protein-protein complexes to gain the deep understanding of binding properties and dynamic fluctuations of complexes for biological functions and (2) examining two important photomachines of photoreceptors (blue-light cryptochrome, UV-light receptor UVR8 and red-light phytochrome) and photoenzyme photolyases. By systematic investigations of these dynamics over a wide time range, we will uncover the entire process of initial signal transduction and reveal the reaction mechanisms and photocycles of phytochrome and UVR8. The new knowledge obtained from these efforts on biological-water dynamics and photoreceptor/photoenzymes photocycles is significant to protein properties, dynamics, and functions involving protein-DNA/protein complexes and signal transduction processes, and more importantly, is critical to practical applications of drug design for a series of diseases such as mental disorder.

Public Health Relevance

Lay Description: Protein dynamics is essential to its biological function. Water-protein interaction is essential for protein stability and flexibility, directly affecting protein folding and misfolding, a process to causing neurodegenerative disease. Two blue-light and UV-light photoreceptors in nature are important via signal transduction to synchronize the circadian clock in animals or to regulate growth and development in plants by cryptochrome and to prevent UV damage by UVR8. Here, we develop a novel method by integrating time-resolved laser spectroscopy and biochemistry/molecular biology to systematically characterize these dynamics over a wide time scale. The new knowledge from these studies is fundamental to the protein stability, dynamics and function of protein-DNA/protein complexes and signal transduction fields and also significant to a series of potential applications such as drug design and prevention of mental disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
3R35GM118332-05S1
Application #
10136754
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Flicker, Paula F
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Ohio State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Zhang, Meng; Wang, Lijuan; Zhong, Dongping (2017) Photolyase: Dynamics and electron-transfer mechanisms of DNA repair. Arch Biochem Biophys 632:158-174
Zhang, Meng; Wang, Lijuan; Zhong, Dongping (2017) Photolyase: Dynamics and Mechanisms of Repair of Sun-Induced DNA Damage. Photochem Photobiol 93:78-92
Zhang, Meng; Wang, Lijuan; Shu, Shi et al. (2016) Bifurcating electron-transfer pathways in DNA photolyases determine the repair quantum yield. Science 354:209-213
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
Faraji, Shirin; Zhong, Dongping; Dreuw, Andreas (2016) Characterization of the Intermediate in and Identification of the Repair Mechanism of (6-4) Photolesions by Photolyases. Angew Chem Int Ed Engl 55:5175-8