Rapid solution of the cryo-EM reconstruction problem by frequency marching

TL;DR

This paper introduces a fast, deterministic Fourier domain method for high-resolution cryo-EM reconstruction that does not require initial guesses and reduces computational effort by frequency marching.

Contribution

A novel frequency marching approach for cryo-EM reconstruction that simplifies and accelerates the process without initial guesses.

Findings

Operates efficiently with modest computational effort.

Achieves high-resolution reconstructions ab initio.

Reduces complexity compared to traditional methods.

Abstract

Determining the three-dimensional structure of proteins and protein complexes at atomic resolution is a fundamental task in structural biology. Over the last decade, remarkable progress has been made using "single particle" cryo-electron microscopy (cryo-EM) for this purpose. In cryo-EM, hundreds of thousands of two-dimensional images are obtained of individual copies of the same particle, each held in a thin sheet of ice at some unknown orientation. Each image corresponds to the noisy projection of the particle's electron-scattering density. The reconstruction of a high-resolution image from this data is typically formulated as a nonlinear, non-convex optimization problem for unknowns which encode the angular pose and lateral offset of each particle. Since there are hundreds of thousands of such parameters, this leads to a very CPU-intensive task---limiting both the number of particle images which can be processed and the number of independent reconstructions which can be carried out for the purpose of statistical validation. Here, we propose a deterministic method for high-resolution reconstruction that operates in an ab initio manner---that is, without the need for an initial guess. It requires a predictable and relatively modest amount of computational effort, by marching out radially in the Fourier domain from low to high frequency, increasing the resolution by a fixed increment at each step.