Any current cryo-EM algorithmic pipeline entails recovering the 3-D structure after particle picking. However, the signal-to-noise ratio of the data, and thus the reliability of particle picking, drops with the molecular mass of the specimens. Accordingly, it is commonly believed that cryo-EM cannot be used to map molecules with a molecular mass below a certain threshold. Challenging this misconception, I will argue that finding the particle picking is not a prerequisite for structure determination and thus small molecules are, at least in principle, within reach of cryo-EM. Then, I will introduce two computational frameworks to bypass particle picking and show numerical results on simulated data.
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