Methods for Cryo-EM Single Particle Reconstruction of Macromolecules having Continuous Heterogeneity

TL;DR

This paper reviews advanced cryo-EM computational methods for reconstructing macromolecular structures exhibiting continuous heterogeneity, addressing the challenge of capturing flexible and transitional states.

Contribution

It provides a comprehensive survey of recent methods developed to handle continuous heterogeneity in cryo-EM single particle analysis.

Findings

Recent methods effectively model flexible regions

Progress in capturing conformational continua

Enhanced understanding of energy landscapes

Abstract

Macromolecules change their shape (conformation) in the process of carrying out their functions. The imaging by cryo-electron microscopy of rapidly-frozen, individual copies of macromolecules (single particles) is a powerful and general approach to understanding the motions and energy landscapes of macromolecules. Widely-used computational methods already allow the recovery of a few distinct conformations from heterogeneous single-particle samples, but the treatment of complex forms of heterogeneity such as the continuum of possible transitory states and flexible regions remains largely an open problem. In recent years there has been a surge of new approaches for treating the more general problem of continuous heterogeneity. This paper surveys the current state of the art in this area.