High throughput laboratory X-ray illumination system for protein crystallography and screening

DESCRIPTION provided by applicant High throughput laboratory x ray illumination system for protein crystallography and screening X ray protein crystallography is the single most effective method to determine macromolecule structures such as proteins The understanding of the three dimensional structure of proteins gives key insight into their functionality and provides essential information for rational drug design which uses information on the structure of an active site of a critical enzyme in a metabolic or regulatory pathway in order to rationally design chemical compounds to inhibit or activate the enzymeandapos s function in order to treat human diseases The structural information from this technique has led to the engineering of new proteins as well as clinical trials for cancer and Alzheimerandapos s drug targets We propose to develop an X ray illumination system comprising a source using a novel D microstructured anode and a high performance ellipsoidal capillary optic with a large solid angle collection The anode provides superior heat dissipation by incorporating microstructures of an x ray producing material embedded within diamond which has outstanding thermal properties and low mass density This illumination system will provide more than X higher x ray flux and flux density at the macromolecular crystal in comparison to state of the art rotating anode sources Additionally it enables production of high flux of X ray spectral lines in a single x ray source t use multi wavelength anomalous diffraction MAD phase techniques that are currently not accessible in a laboratory system The proposed phase I project is a proof of principle demonstration that such a microstructured anode can indeed be manufactured and to validate its thermal dissipation advantages At least ten prototypes of the novel microstructured anode will be fabricated using copper microstructures embedded in diamond for the Phase I prototypes Furthermore we will confirm and assess the thermal mechanical properties through finite element modeling and empirical measurement during thermal cycling of the prototypes PUBLIC HEALTH RELEVANCE This project proposes to develop a high flux laboratory X ray illumination system for protein crystallography comprising a high brightness D microstructued anode x ray source and x ray optics with substantially higher throughput than the existing laboratory protein crystallography systems The intended impact is to enable faster screening of crystals improve speed and sensitivity in the collection of protein structural information and to increase turnaround time for fragment based drug discovery by improving the flux at the protein by over ten times Knowledge of protein structure is critical for the efficient design of drugs e for cancer and neurodegenerative diseases and for protein engineering