Nien-hui Ge - US grants

In this CAREER award, co-funded by the Experimental Physical Chemistry Program of the Chemistry Division and the Molecular Biophysics Program of the Division of Molecular and Cellular Biosciences, Prof. Nien-Hui Ge of the University of California, Irvine and her post-doctoral and graduate research students will probe the conformational distributions of peptides using multidimensional infrared spectroscopy. The ultimate goal of this research is to uncover the details of how proteins fold and unfold.

In addition to her research activities, Prof. Ge will construct an online infrared resource for use in education. The resource will include a database of both ordinary and multidimensional infrared spectra. The resource's most unique feature will be the incorporation of a multidimensional infrared simulator and interactive tutorials designed for use by non-experts. The audience for the online resource includes undergraduate and graduate physical chemistry students, as well as members of the biophysical research community interested in learning how to apply the methods of multidimensional infrared spectroscopy to their own research problems.

The investigator and his colleagues propose a new paradigm-shifting approach towards high resolution and high contrast imaging, which combines revolutions in magnetic resonance imaging (MRI) and optical imaging with equally cutting edge mathematical developments.
The approach uses non-linear feedback between the detector and the sample, so that the measured field is fed back to the MRI magnet. The unstable feedback increases the dynamical contrast between normal and cancerous cells. This highly nontraditional approach will be complemented by incorporating compressed sensing, a data analysis technique where mathematical algorithms are used to extract specific features and images from a relatively small number of measurements.
Finally, multiple sources and detectors, which coupled with compressed sensing and feedback imaging can collect data in parallel will be implemented together, and modern filter-diagonalization techniques will be used to synthesize the data leading to faster images.

Overall, the research and development that the principal investigator and his colleagues propose will revolutionize MRI. By applying nontraditional measurement and imaging technique, the contrast between tumors and normal areas will be increased many fold. The increase will be based on the same physical phenomena, chaos, that is used to by birds and jet fighters to quickly switch their direction. The revolutionary paradigm will will eventually make it much cheaper and faster to do an MRI scan, thereby having enormously broad impacts. In 2008, an estimated 1,680,000 people in the U.S. will be diagnosed with cancer, and approximately 670,000 people will die. Between 10%-35% could have been saved with earlier detection.
This highlights the need for improved early detection methods, which could have saved many patients. A large (2-5 or more) reduction MRI acquisition time, which is not feasible with conventional methods, coupled with the enhanced feature resolution native to the proposed approach, will allow for faster and cheaper cancer screening, which is crucial to improved early detection and thus reducing deaths due to cancer. Besides cancer detection, there are numerous other imaging applications that stand to benefit from significantly decreased scan time and cost, such as industrial sensing (for example uniformity of fruits in agriculture) and homeland security applications, including highly sensitive detection of concealed materials.

In this award supported by the Chemistry of Life Processes Program, Professor Nien-Hui Ge of the University of California at Irvine will use femtosecond multidimensional infrared (MultiD IR) spectroscopy to study the conformational dynamics, distributions, and folding of peptides. The goal is to provide detailed knowledge of protein structure and dynamics that is essential to the understanding of biological processes. The proposed work includes investigating the interplay between helical and extended structures, determining conformational distributions of nonfolding peptides, studying the association of supercoiled protein motifs, and elucidating protein-membrane interactions. MultiD IR experiments will access the backbone and side chain vibrational modes of peptides, and provide data that reveal the angles, distances, and correlations between structural units. Isotope editing at selected locations will be employed to enhance the spatial resolution, facilitate the assignment of resonances, and extend the method to larger peptides and tertiary contacts. The effects of temperature, pH, solvent, and chain length will be investigated to understand the factors that control protein stability.
MultiD IR spectroscopy is a relatively new technique that complements NMR and X-ray methods, with the capability of probing the structure in situ as it evolves over a wide range of time scales, from femtosecond to millisecond. Applying this technique to the study of peptides will allow us to gain insights into rapid conformational fluctuations and transitions, not readily amenable to conventional techniques. Such experimental data are much needed for verification of theoretical predictions and validation of the next generation of force fields. Further development of two-color MultiD IR methods, analogous to heteronuclear NMR, will allow direct probing of coupling between vibrators of very different frequencies. Its application to the amide vibrational modes will enable conformational determination with higher accuracy. These studies will provide detailed information on peptide structure and dynamics, and contribute to the understanding of protein folding. Graduate students and postdoctoral researchers participating in the research will gain valuable experience with advanced laser techniques and core physical sciences that can strengthen their future career development. Efforts on maintaining an online spectrum database and contributing lectures and laboratory courses for K-12 students will be continued.

This Major Research Instrumentation award supports the acquisition of an ultrafast multimodal spectroscopy system. This system enables advanced time-resolved spectroscopy experiments, a key capability in material and molecular research. The system will be placed in the Laser Spectroscopy Facility (LSF), housed in the Department of Chemistry of the University of California Irvine. Traditionally, ultrafast lasers and spectroscopy have not been part of user facilities because former ultrafast laser technologies were too complex and unreliable to support many users. Consequently, the user community of ultrafast technologies has remained small, and the unique research capabilities of ultrafast optical techniques have remained inaccessible to an audience interested in such capabilities. In this Program, a state-of-the-art ultrafast laser system is made accessible through a three-pronged model based on optimized facility conditions, strong user support and a partnership with industry. This model addresses past limitations to make ultrafast laser technology and its research capabilities accessible to a much broader community of researchers. In making the technology available to a much larger user base, the impact of ultrafast spectroscopy is significantly amplified. The Program ensures broad exposure and dissemination of ultrafast spectroscopy capabilities. On the UCI campus alone, the Laser Spectroscopy Facility (LSF) in which the system will be housed supports more than 300 users, and serves 13 departments on campus. By leveraging strong connections with institutions and companies neighboring UCI, a large community of researchers will have access to the ultrafast spectroscopy capabilities offered through the facility. The impact of the requested technology is further fortified by a strong user training program, established channels of dissemination, and an outreach program designed around the ultrafast spectroscopy instrument

The most fundamental processes in matter evolve on ultrafast time scales. Examples include the making and breaking of chemical bonds, conformational motions of molecules, evolution of optical excitations, and electron transfer processes. These phenomena form the mechanistic basis of scientific challenges in chemistry, biology and materials science: designing efficient catalysts, understanding nature's solution to light harvesting materials, and optimizing the efficiency of solar cells, to name a few. Ultrafast laser technologies have proven indispensable for meeting these challenges, as they provide direct recordings of such fast fundamental processes. Consequently, the demand for ultrafast spectroscopy is growing, as an increasingly expanding pool of chemists, chemical engineers, physicists, and biologists come to rely on this technology. The goal of this Program is to bring the unique capabilities of ultrafast laser science to a broad community of researchers. This goal is achieved by implementing a three-pronged model: 1) Acquisitions of a commercial ultrafast laser light source and nonlinear optical spectrometer, with unprecedented performance, versatility, stability, and simplicity of operation. The system is made available through a staffed user facility at the University of California, Irvine (UCI); 2) A partnership with Newport Optics, the supplier of the instrument. The partnership establishes a push-pull mechanism between technology and application for impacting a broad community beyond the users at UCI; 3) The Ultrafast Consultation Board (UCB), a team of experimental and theoretical ultrafast spectroscopists who provide general assistance, technical guidance, mentoring and help with the interpretation of data. By providing depth to the analysis of acquired spectroscopic data, the UCB bolsters the scientific impact of measurements made by non-experts, expands the user base, and magnifies the breadth of research topics supported by this Program.

Nitrogenases are important enzymes that catalyze the conversion of nitrogen to ammonia and play key roles in the global nitrogen cycle. Recently, they have also been shown to convert carbon monoxide (CO) to hydrocarbons and, therefore, are recognized as important candidates for the production of biofuels. With this award, the Chemistry of Life Processes Program in the Division of Chemistry at NSF is funding Professor Nien-Hui Ge from the University of California, Irvine, to investigate how CO binds to and interacts with nitrogenases. Although nitrogenases have been well studied, the detailed mechanisms for CO binding and reactions are still lacking. This project will apply state-of-the-art ultrafast vibrational spectroscopy to capture molecular motions using laser pulses at "shutter speeds" faster than one-trillionth of a second. These snap-shots provide new and much needed information on the molecular structure and transient dynamics of CO and nitrogenases as they bind and interact with each other. Graduate students participating in the research gain valuable training with advanced laser techniques and core physical sciences to strengthen their career development. This project is also integrated with outreach efforts that engage K-12 students through scientific demonstrations.

This project is undertaken to gain a molecular picture of CO binding to molybdenum- and vanadium-dependent nitrogenases by novel applications of ultrafast two-dimensional infrared spectroscopy and a variety of transient measurements. The high time resolution of these techniques allows the study of rapid structural fluctuations and transitions of the enzyme. When combined with computational modeling, these experiments reveal the structure of CO at binding sites, elucidate local environment around the cofactor, and establish connectivities between different CO species. Detailed structural and dynamic information obtained from this project provides new insight and helps to establish a unified mechanism for CO binding to nitrogenases.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.