Merging conformational landscapes in a single consensus space with FlexConsensus algorithm.

Abstract

Structural heterogeneity analysis in cryogenic electron microscopy is experiencing a breakthrough in estimating more accurate, richer and interpretable conformational landscapes derived from experimental data. The emergence of new methods designed to tackle the heterogeneity challenge reflects this new paradigm, enabling users to gain a better understanding of protein dynamics. However, the question of how intrinsically different heterogeneity algorithms compare remains unsolved, which is crucial for determining the reliability, stability and correctness of the estimated conformational landscapes. Here, to overcome the previous challenge, we introduce FlexConsenus: a multi-autoencoder neural network able to learn the commonalities and differences among several conformational landscapes, enabling them to be placed in a shared consensus space with enhanced reliability. The consensus space enables the measurement of reproducibility in heterogeneity estimations, allowing users to either focus their analysis on particles with a stable estimation of their structural variability or concentrate on specific particle subsets detected by only certain methods.