Toward single particle reconstruction without particle picking: Breaking the detection limit

TL;DR

This paper proposes a novel autocorrelation-based method for reconstructing biological macromolecular structures directly from cryo-EM micrographs without particle detection, aiming to improve analysis of small molecules.

Contribution

It introduces a new approach that bypasses particle detection, enabling direct structure reconstruction from micrographs, especially beneficial for small molecules with high noise levels.

Findings

Successful proof-of-concept demonstration

Allows online, streaming processing of micrographs

Highlights challenges for practical implementation

Abstract

Single-particle cryo-electron microscopy (cryo-EM) has recently joined X-ray crystallography and NMR spectroscopy as a high-resolution structural method to resolve biological macromolecules. In a cryo-EM experiment, the microscope produces images called micrographs. Projections of the molecule of interest are embedded in the micrographs at unknown locations, and under unknown viewing directions. Standard imaging techniques first locate these projections (detection) and then reconstruct the 3-D structure from them. Unfortunately, high noise levels hinder detection. When reliable detection is rendered impossible, the standard techniques fail. This is a problem, especially for small molecules. In this paper, we pursue a radically different approach: we contend that the structure could, in principle, be reconstructed directly from the micrographs, without intermediate detection. The aim is to bring small molecules within reach for cryo-EM. To this end, we design an autocorrelation analysis technique that allows to go directly from the micrographs to the sought structures. This involves only one pass over the micrographs, allowing online, streaming processing for large experiments. We show numerical results and discuss challenges that lay ahead to turn this proof-of-concept into a complementary approach to state-of-the-art algorithms.