Guide for determination of protein structural ensembles by combining cryo-EM data with metadynamics

Metadynamics electron microscopy metaInference (MEMMI) is an integrative structural biology method that enables a rapid and accurate characterization of protein structural dynamics at the atomic level and the error in the cryo-EM experimental data, even in cases where conformations are separated by high energy barriers. It achieves this by incorporating (a) cryo-electron microscopy electron density maps with (b) metadynamic-enhanced-sampling molecular dynamics. Here, I showcase the setup and analysis protocol of MEMMI, used to discover the atomistic structural ensemble and error in the cryo-EM electron density map of the fuzzy coat of IAPP, a fibril implicated in type II diabetes.

Automated summary

Metadynamics electron microscopy metaInference (MEMMI) is an integrative structural biology method that combines cryo-electron microscopy electron density maps with metadynamic-enhanced-sampling molecular dynamics to characterize protein structural dynamics and errors in cryo-EM experimental data. It can accurately determine atomistic structural ensembles and errors, even in cases where conformations are separated by high energy barriers. In this study, MEMMI is used to analyze the fuzzy coat of IAPP, a fibril associated with type II diabetes.