Revealing More with Less: Dose Efficiency in Electron Imaging

Single-particle cryogenic electron microscopy (cryo-EM) has experienced remarkable advancements in the past twenty years, emerging as a powerful technique for solving molecular structures at sub-4 Å resolutions critical for atomic model building. However, challenges persist due to low scattering contrast in biomolecules and their radiation sensitivity, necessitating low-dose, low-signal imaging and the averaging of thousands of noisy, randomly oriented particle images. Here, we compare the dose efficiency of plane-wave electron coherent diffractive imaging (CDI), ptychography, and high-resolution transmission electron microscopy (HRTEM) on weak-phase biological molecules by simulating two-dimensional images and estimating their resolution with the use of the Fourier ring correlation (FRC) as a function of electron dose. Our results illustrate the potential for adopting ptychography in single-particle cryo-EM for the next generation of electron microscopes for molecular imaging.