The outcome of this phase 1 project will yield a turnkey system for spectroscopy/polarimetry in the terahertz (0.8-3.0 THz) frequency range, designed to support development of new drugs. This system will directly probe protein vibrations using polarized terahertz radiation, allowing researchers to rapidly characterize intramolecular vibrations, which will help identify sites on proteins for potential drug targets. By looking at differences in absorption of polarized light between different relative molecular orientations, vibrational resonances can be isolated from the isotropic background which generally obscure these features. This measurement system will enable a researcher to readily mount a protein microcrystal and immediately have the intramolecular vibrational fingerprint to readily see if and how this fingerprint has changed with single point mutations or binding. This characterization of intramolecular dynamics will be done without the need to introduce an external tag to the system under study. The main technological hurdle that will be addressed during this phase I project that will be crucial to the commercialization is the vast simplification of the data acquisition. A high brightness terahertz source will be developed that will allow intensity based detection of the spectroscopic data. This source will use a high power fiber laser and a quasi-phase matched nonlinear crystal to generate tunable, narrowband terahertz output. The second technological improvement will be the development of polarization control module, which will allow data acquisition without moving the sample, which is necessary for fast data collection. Finally, an integrated sample holder/detection module will be developed that allows users to easily change samples without disturbing the alignment into the detector. Information on long range structural vibrations is of particular interest in design of allosteric drugs, which bind to a location distant from the active site on a molecule. The current interest in allosteric drugs is due to their distinct advantages over orthosteric drugs (drugs that bind directly to the active site). Currently there are research efforts dedicated to gaining a better fundamental understanding of the mechanisms behind allostery, with the goal of eventually predicting how action at distant sites modulates protein activity. This information will stream line drug discovery efforts, reduce costs for the drug industry and cost of medications for the patients. More importantly, it will have a much broader societal impact by expediting the drug discovery process and making new drugs available faster.
Public Health Relevance Statement: NARRATIVE This project aims to produce an instrument that is capable of rapidly characterizing long-range structural vibrations in proteins. In the long term, the information obtained from this instrument can be used in conjunction with computational models to identify binding sites on proteins for potential drugs.
Project Terms: absorption; Active Sites; Address; Anisotropy; base; Benchmarking; Binding; Binding Sites; Comb animal structure; commercialization; Complex; Computer Simulation; Crystallization; data acquisition; Data Collection; Databases; design; Detection; detector; Development; Distant; Drug Costs; drug discovery; Drug Industry; Drug Targeting; Fiber; Fingerprint; Frequencies; Goals; Industrialization; instrument; interest; Lasers; Location; Measurement; Measures; Molecular; Motion; novel; novel therapeutics; Optics; Outcome; Output; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiologic pulse; Point Mutation; polarimetry; polarized light; Process; Proteins; prototype; Radiation; Research; Research Personnel; Resolution; Sampling; Scanning; Signal Transduction; Site; Source; spectroscopic data; Spectrum Analysis; Stream; System; vibration
