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"High-speed atomic force microscopy (HS-AFM) is the only experimental technique to directly watch proteins in dynamic action. However, as a surface scanning technique with limited spatial resolution, HS-AFM will inevitably provide insufficient information for detailed atomistic understanding of biomolecular function. Despite previous efforts in computational modeling attempting to overcome such limitations, successful applications to retrieve atomistic-level information from measurements are practically absent.
A research team ... presents a computational framework and its software implementation allowing to infer 3D atomistic models of dynamic protein conformations from AFM topography imaging. ..."
From the abstract:
"High-speed atomic force microscopy (HS-AFM) experiments allow direct observation of biomolecular dynamics at the single-molecule level, acquiring a large amount of topographic imaging data that visualizes changes in the molecular surface during functional activity over an extended period of time. Since images have no atomistic resolution, a major challenge has been to develop post-experimental computational methods to infer atomistic information from measurements.
The recently developed NMFF-AFM flexible fitting method provides a computationally efficient approach promising to infer atomistic-precision models of conformational dynamics from resolution-limited AFM imaging data.
We report the software integration of this method into the well-established BioAFMviewer platform and demonstrate its first applications to experimental HS-AFM imaging data.
To facilitate applications, we developed a direct workflow from raw experimental AFM data to the visualization and analysis of fitting results. The presented applications to experimental data of a single protein domain, a protein complex, and a megadalton-sized protein filament demonstrate the versatility of NMFF-AFM modeling to reproduce large-amplitude conformational motions of biomolecular dynamics from HS-AFM imaging.
As a first step toward automated large-scale analysis of AFM imaging data, we furthermore demonstrate reconstruction of an atomistic molecular movie of protein dynamics, involving large-amplitude conformational transitions, from a measured HS-AFM movie sequence.
Implementation of flexible fitting within the stand-alone user-friendly interactive BioAFMviewer software provides the opportunity for a broad range of applications to facilitate the understanding of resolution-limited HS-AFM measurements."
Graphical abstract
Figure 2. HECT domain large-amplitude conformational transition.
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