Abstract: The present disclosure provides methods of collecting electron diffraction patterns from nanocrystals to obtain a three-dimensional structural model of a compound, as well as methods of identifying compounds and methods of determining polymorphic forms. In addition, the present disclosure provides methods of characterizing a first compound from a sample, as well as methods of screening compounds from a sample. The present disclosure also provides systems for characterizing a compound from a sample, which systems include modules for high-performance liquid chromatography, dispensing, and electron microscopy.

Abstract: An integrated microcrystal electron diffraction system and method are provided that include an electron source, a sample assembly configured to retain a sample, a camera assembly, and a control system. The control system pre-screens the sample on the sample assembly, collects image data of the sample via the camera assembly, and outputs microcrystal electron diffraction data based on the image data. Pre-screening includes capturing at least one pre-screen diffraction image of the sample; determining a position for the sample for imaging based on the at least one pre-screen diffraction image; and controlling the sample assembly to position the sample at the position. Collecting the image data includes generating an electron beam towards the sample at the position; rotating the sample assembly; and capturing, by the camera assembly, scatterings of the electron beam by the sample as diffraction images while the sample assembly is rotated.

Abstract: Methods of introducing a small molecule into a crystal of a macromolecule, of obtaining a microcrystal having a macromolecule and a small molecule from a crystal of the macromolecule, of determining a structural model for a complex having a macromolecule and a small molecule, of identifying a small molecule that complexes with a macromolecule, and of screening a library of small molecules for their binding to a macromolecule are disclosed.

Abstract: Methods of collecting diffractionpatterns from a microcrystal having an ordered array of a molecule are disclosed, which nclude using an exposure rate of at most 0.02 electrons per square angstrom per second on the microcrystal and using a direct electron etector to record electron diffraction patterns. Also disclosed are methods of determining a structural model for a molecule, identifying a material present in a trace amount within a sample, identifying a polymorph, and identifying the stereochemistry of a molecule.

Abstract: A sample preparation method includes disposing a microcrystal on an electrically conductive grid, coating the microcrystal with an electrically conductive material to yield a coated microcrystal, milling the coated microcrystal with a first ion beam to yield a milled microcrystal, and polishing the milled microcrystal with a second ion beam to yield a polished microcrystal. A length of a side of the milled microcrystal is between about 250 nm and about 500 nm, and a length of the corresponding side of the polished microcrystal is between about 150 nm and about 250 nm. Assessing the crystal structure of the polished microcrystal includes rotating the polished microcrystal while accelerating electrons toward the polished microcrystal, diffracting the electrons from the polished microcrystal to yield a multiplicity of diffraction patterns, and assessing, from the multiplicity of diffraction patterns, the crystal structure of the polished microcrystal.

Abstract: A sample preparation method includes disposing a microcrystal on an electrically conductive grid, coating the microcrystal with an electrically conductive material to yield a coated microcrystal, milling the coated microcrystal with a first ion beam to yield a milled microcrystal, and polishing the milled microcrystal with a second ion beam to yield a polished microcrystal. A length of a side of the milled microcrystal is between about 250 nm and about 500 nm, and a length of the corresponding side of the polished microcrystal is between about 150 nm and about 250 nm. Assessing the crystal structure of the polished microcrystal includes rotating the polished microcrystal while accelerating electrons toward the polished microcrystal, diffracting the electrons from the polished microcrystal to yield a multiplicity of diffraction patterns, and assessing, from the multiplicity of diffraction patterns, the crystal structure of the polished microcrystal.

Abstract: An apparatus for a transmission electron microscope includes a housing configured to be attached to the transmission electron microscope; a plunger received in the housing and movable relative to the housing; a first set of pieces coupled to the plunger, the first piece being configured to move relative to the housing in response to the plunger moving relative to the housing; and a second set of pieces positioned in a fixed spatial relationship relative to each other, the second set of pieces and the first set of pieces forming a perimeter of an opening, an extent of the opening being continuously variable by moving the first set of piece relative to the second set of pieces.

Abstract: This document relates to two dimensional (2D) protein arrays can be used in biotechnology applications, as well as methods of making and using 2D protein arrays. In some cases, a 2D protein array can be used to evaluate (e.g., image) a structure (e.g., a three dimensional (3D) structure) of a protein of interest. In some cases, a 2D protein array can be used to evaluate (e.g., characterize) protein-protein interactions (e.g., stable interactions vs. transient interactions). In some cases, a 2D protein array can be used to evaluate a binding domain in a protein of interest. In some cases, a 2D protein array can be used to evaluate (e.g., identify) binding targets and/or partners of a protein of interest.