Our bodies are alive with activity and full of proteins trapped in fatty membranes or floating in and out of watery cells. Scientists have now, for the first time, captured the dance between the two: a liquid tango in which proteins and fats move normally in cells.
“We are going beyond simply taking single snapshots, which give structure but not dynamics, to continuously record molecules in water, their native state,” says Qian Chen, a materials scientist and engineer at the University of Illinois Urbana -Champaign (UIUC), who led the team and describes their work as “making movies.”
“We can really see how proteins change their configuration and, in this case, how the entire protein-lipid self-assembled structure fluctuates over time.”
By modifying a widely used imaging technique called transmission electron microscopy, Chen’s team captured the vibrant choreography of “nanodiscs” of membrane proteins in a liquid. These nanodiscs are made of proteins embedded in a lipid bilayer that resembles the cell membranes in which they are usually found.
The team dubbed their method “electronic videography” and validated the video data by comparing it to atomic-level computer models of how molecules should move based on the laws of physics.
The movement of membrane-bound proteins was thought to be quite limited, given the way lipids hold them in place. However, the researchers observed that interactions between proteins and lipids occur over much larger distances than previously thought possible.
Membrane proteins are the gatekeepers, sensors and signal receivers of the cell, so the technique could lead to huge advances in our understanding of how they work.
With existing techniques, proteins are usually frozen or crystallized so that they do not move and blur the image, nor are they damaged by the X-rays or electron beams used to image them. This provides a lifeless image of a static protein that normally bends and folds, leaving scientists to infer how it interacts with other molecules based on its structure.
Alternatively, some imaging techniques use a fluorescent molecular tag to follow molecules as they move, rather than observing the protein directly.
In this case, the researchers caged a drop of water inside two thin sheets of graphene to protect it from the vacuum of the electron microscope. Suspended in the water drop were unlabeled nanodiscs of proteins and lipids, which the team saw “dancing” together as if in their natural aqueous environment.
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Materials scientists have tried for at least a decade to film the activity of biological molecules in liquids, but have failed to clearly observe the continuous dynamics of proteins.
With some careful modifications to the approach, Chen and colleagues imaged their protein-lipid assemblies in real time and for minutes, not microseconds. Importantly, they slowed down the rate at which electrons penetrate the sample and worked on the graphene scaffold, to successfully film the protein-lipid complex in action.
“Currently, this is really the only experimental way to film this kind of motion over time,” says UIUC materials engineering graduate student John Smith, first author of the paper.
“Life is in a liquid state and is in motion. We are trying to get to the finer details of that connection in an experimental way.”
As for other efforts, improved imaging techniques are revealing incredible detail about all kinds of microscopic events, from observing how a virus’s outer coat takes shape to capturing the moment proteins collapse into clumps in diseases such as Alzheimer’s.
Add artificial intelligence to the mix, to predict the 3D shape of nearly every protein known to science, and it certainly seems like a new era of biological research has opened up.
The research was published in Advances in science.