Electron Videography of a Lipid–Protein Tango

Biological phenomena ranging from enzymatic catalysis to synaptic transmission find their origins in the morphological fluctuations of biomolecules and biomolecular assemblies in liquid water. However, directly imaging these nanoscopic dynamics without probes or labels has been a fundamental methodological challenge. Here we developed an approach for ‘molecular videography’—combining liquid-phase transmission electron microscopy with molecular modelling—with which we filmed the nanoscale morphological fluctuations of individual, freely suspended, and unlabelled membrane protein nanodiscs in liquid. These unprecedented observations enabled us to quantify fingerprints of nanoscale lipid–protein interactions directly, revealing that nanodisc shape undulations are defined by the molecular mechanics of encircling scaffold proteins, whereas lipid interactions with a membrane protein reach across surprisingly long ranges to delineate dynamically modified membrane domains and increase nanodisc stability. Overall, this work illustrates an experimental approach to image, quantify, and understand biomolecular dynamics at the nanometre scale.