High-throughput biomolecular crystallization and biomolecular crystal screening

A method for ejecting a different reagent-containing fluid from each of a plurality of fluid reservoirs toward designated sites on a substrate surface to form a combinatorial array of fluid samples on the substrate, containing a biomacromolecule of interest for crystallization, the method comprising the steps of:

• (a) positioning an acoustic ejector so as to be in acoustically coupled relationship to a first reservoir containing a first reagent-containing fluid;
• (b) activating the ejector to generate acoustic radiation having a focal point near the surface of the first fluid, thereby ejecting a first droplet of the first reagent-containing fluid from the first reservoir toward a first designated site on the substrate surface, whereby the droplet adheres to the designated site;
• (c) repositioning the ejector so as to alter the relative positions of the ejector and the first reservoir and to place the ejector in acoustically coupled relationship to a second reservoir containing a second reagent-containing fluid different from the first;
• (d) activating the ejector as in step (b) to eject a second droplet of the second reagent-containing fluid from the second reservoir toward the first designated site on the substrate surface, whereby the second droplet adheres to the designated site and mixes with the first droplet;
• (e) repeating steps (c) and (d) with additional reservoirs each containing a different reagent-containing fluid until the first designated site on the substrate surface has a fluid sample adhering thereto;
• and
• (f) repeating steps (a) through (e) for the remaining designated sites of the array until each site has a fluid sample adhering thereto,
• wherein each fluid volume sample contains the biomacromolecule of interest for crystallization and each fluid sample occupying a designated site whereby the fluid samples are arrayed on the substrate surface at the designated sites and the composition and chemical conditions at each site are known from the steps of the method and the reagent-containing fluids deposited.

A system for combinatorial experiments to crystallize a moiety of interest and detect crystallization of the moiety of interest, the system comprising:

• a plurality of sites arrayed on a substrate;
• a plurality of reservoirs each adapted to contain a reagent-containing fluid;
• an ejector that is moveable relative to the reservoirs comprising an acoustic radiation generator for generating acoustic radiation and a focusing means for focusing the acoustic radiation at a focal point near the fluid surface in each of the reservoirs;
• and
• a means for positioning the ejector in acoustic coupling relationship to each of the reservoirs;
• and
• means for detecting crystallization of the moiety of interest;
• wherein
• one or more of the materials arrayed on the substrate are contacted with one or more reagent-containing fluids by acoustic ejection, and any physical or chemical change detected at a site upon said contacting denotes a screening result for the material present at said site contacted with said one or more reagent-containing fluids.