I-Corps: Microfluidics for Protein Crystallization and X-ray Diffraction

Brandeis University, Waltham MA

Investigators

Abstract

The broader impact/commercial potential of this I-Corps project is to provide pharmaceutical companies and life scientists with a cost effective and fast approach for determining the high-resolution protein structure by X-ray crystallography. Production of high-resolution structures of proteins is one the main steps in structure-based drug design. Although cost reduction and efficiency improvements are the important benefits of structure-based drug design, the lack of generalized methods for high quality, fast and low-cost crystal production is still a major struggle in this process. Microfluidics, is a powerful liquid handling tool that reduces the amount of solution in a screening experiment to nanoliters, have been introduced to the protein crystallization market earlier. However, none of these approaches have penetrated the market because of the high cost to performance ratio. Our innovation is an x-ray transparent microfluidic chip for protein crystallization which is less expensive, easier to operate and more performant in comparison to the current market solutions. By commercializing this device and introducing it to the market, pharmaceutical companies and life scientists will reduce the time and money spent to determine the high-resolution structure of proteins from x-ray diffraction, which is a current bottleneck in structure-based drug discovery. This I-Corps project introduces an inexpensive, x-ray transparent microfluidic chip for protein crystallization. For many medical and biological applications, such as pharmaceutical engineering, the molecular structure of a protein is essential. The most accurate way to determine protein structure is X-ray crystallography, a process that requires the analysis of X-ray diffraction patterns of protein crystals. However, protein crystallization remains challenging because each protein has its own phase diagram, thus, many different conditions should be tried to find the optimal conditions for protein crystallization. Our technology addresses four core challenges in protein crystallization; it (1) screens chemical conditions for protein crystal stability, (2) produces crystals using optimized processing kinetics, (3) obtains structure with room temperature crystals, and (4) avoids crystal handling by diffracting on chip. On-chip X-ray diffraction has been demonstrated for our protein crystallization chips. Prototypes of our first design have been made and have been tested for protein crystallization with one specific solution. Our design is a liquid handling chip with multiple advantages over current microfluidic chips. It is built from inexpensive bio-compatible material via a rapid fabrication procedure and it can be altered as needed based on the customer need. 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.