 Abstract Creo-electron tomography, Creo-ET, allows observing macromolecular complexes in their natural environment. Subtamogram averaging, StA, can extract the 3D structure of abundant macromolecular complexes, but it is limited by the small number of complexes observed. To overcome this limitation, alternative methods are being explored to analyze the continuity of conformational landscapes provided by Institute Creo-ET studies. One such approach is MDTOMO, which uses molecular dynamics, MD, simulations to generate an atomic scale model of conformational variability and the corresponding free energy landscape from a given set of Creo-ET sub-tomograms. This method has been successfully applied to both synthetic and in-situ SARS-CoV-2 spike data sets. It provides insight into the dynamic properties of macromolecules, which could be used for structure-based drug discovery. This article was authored by Remy Vujmo, Isabel Ruya, and Slava Kojonic.