TEM MicroED Platform for High-Throughput Microcrystal Screening
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for obtaining atomic-resolution crystal structures of small molecules and drug-protein complexes face challenges due to the difficulty in growing large, high-quality crystals, leading to time-consuming and inefficient screening processes, especially when samples fail to crystallize readily.
Innovation Solution
Combining microarraying technology with microED to perform high-throughput analysis of drug-protein interactions and crystalline sponge soaking, enabling the deposition of hundreds of microcrystals or crystalline sponges onto a single TEM grid for rapid screening using microED.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If single crystal X-ray diffraction (SCXRD) is used to obtain atomic-resolution crystal structures, then measurement precision is improved, but productivity deteriorates due to time-consuming crystal growth screening
Solution Approach 1:
The invention segments the crystal screening process by microarraying hundreds of microcrystals onto a single TEM grid, allowing parallel analysis of multiple samples in one experiment. This segmentation transforms the sequential screening bottleneck into a parallelized high-throughput workflow while maintaining microED's atomic-resolution capability.
2Measurement precision
If large single crystals are grown for SCXRD analysis, then measurement precision is improved, but loss of time increases due to extensive screening requirements
Solution Approach 1:
The invention uses disposable microcrystals (approximately -1 μm3 or less) that do not require extensive growth time. These microcrystals can be obtained from failed SCXRD trials or amorphous powders, eliminating the time-consuming crystal growth step while still providing sufficient quality for microED analysis.
3Adaptability or versatility
If crystal soaking is performed with large single crystals, then drug-protein interaction study is enabled, but diffusion of small molecule analyte deteriorates
Solution Approach 1:
The invention transitions from studying drug-protein interactions in large 3D single crystals to analyzing microcrystals on a 2D TEM grid surface. This dimensional change dramatically increases the surface-area-to-volume ratio, enabling rapid diffusion of small molecule analytes into the crystal lattice during soaking while maintaining the ability to study drug-protein interactions.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach significantly reduces the time required for sample screening and increases the throughput of data collection by allowing simultaneous analysis of multiple samples, overcoming the limitations of traditional crystallographic methods.
Implementation Method 1
microED for diffraction
Data Source
AI summary
The present disclosure relates to methods of obtaining electron diffraction data of microcrystalline samples.