Within every living cell on earth, countless microscopic “molecular machines” are at work carrying out cellular functions. They convert between different types of energy, transport materials and assemble complex structures. When these complex machines malfunction it can lead to disease, so scientists are working to understand both how molecular machines work and why they have evolved the way they have. This knowledge could help researchers design nanomachines to do the work of nature, only better.
David Sivak, Simon Fraser University (SFU) physics professor and Canada Research Chair in Nonequilibrium Statistical Biophysics, leads the Sivak Group at SFU. His interdisciplinary research on the energetics and dynamics of complex biological systems spans molecular biology and biochemistry, chemistry, physics and mathematics.
Matthew Leighton is a physicist and SFU PhD student researching the physics of living organisms. He is working with professor Sivak to investigate the nonequilibrium physics of molecular machines.
Leighton and Sivak recently published a paper outlining a new “theoretical microscope” for peering into the inner workings of molecular machines. Their new tools let them zoom in on complex machines and resolve details about the nanoscale parts they are made of. Inferring Subsystem Efficiencies in Bipartite Molecular Machines was recently published in Physical Review Letters. Access the PDF version here.
We spoke with Matthew Leighton and David Sivak about their research.
What research question or unknown did you set out to solve?
Molecular machines are key contributors to a wide range of important cellular functions, converting energy between different forms such as electrical, chemical, and mechanical energy. For example, the molecular machine FoF1-ATP synthase converts a proton gradient across the mitochondrial membrane into chemical energy by synthesizing molecules of ATP (the energy currency of the cell). Like many biological molecular machines, FoF1-ATP synthase is composed of two coupled components which exchange energy and information with each other, called Fo and F1. Until now these internal details have been inaccessible experimentally, with researchers either studying the molecular machine as a whole, or dissecting it to study individual parts in isolation.
Tell us more about your groundbreaking research.
In this new work, we outline a new method for inferring efficiencies of individual components from experimental data, which we showcase by obtaining the first in vivo estimates for the efficiencies of Fo and F1. For the first time, critical internal details can now be resolved from observations of the whole machine operating in its natural context. Thus, we can see not only the efficiency of the machine as a whole, but also the efficiencies of all of the parts making up the machine. This allows us to zoom in on a complex machine to determine the source of inefficiencies.
How might your research be applied to developing technologies that support cellular function?
In the near term, the most direct application of our work would be to use our results to infer subsystem efficiencies in experimentally realized artificial molecular machines. In recent years, it has become increasingly possible to engineer complex nanomachines from scratch, and quantifying their efficiency is essential. Typically chemists or engineers will synthesize a composite molecular machine from scratch, and find that their machine is highly inefficient. Using our new tools, these researchers will be able to zoom in on the individual parts of the machine and figure out where the inefficiency is coming from. This means that they can focus their design efforts on specific parts of the machine, rather than redesigning the whole thing from scratch.
In the longer term, we’d like to apply our tools to more biological molecular machines. By more closely examining these machines which have been optimized by evolution over billions of years, we hope to learn more general design principles for synthetic nanomachines.
To Matthew: How did you discover the Sivak Group and SFU? Has your experience at SFU shaped the direction of your research?
I was trying to decide where to apply to grad school back in fall 2019, and looking at theoretical biophysics groups all over the country. I met one of David’s former PhD students, Steve Large, at the Canadian Undergraduate Physics Conference, and really liked what I heard from him about the research going on in the Sivak Group. From there I got in touch with David to apply for a spot in the group.
The physics department at SFU is home to several strong biophysics groups, which regularly come together for both formal events like our weekly biophysics seminar as well as more informal conversations. This environment leads to a lot of bouncing ideas around, which helps to sharpen ideas as they form, and provides much more exposure to new ideas than we would get otherwise.
To David: Tell us about your experience collaborating with graduate students in your lab. Has working with students taken your research in new directions?
Working together with graduate students—and more broadly with all who train in the lab, from undergrads to postdocs—is the main way I engage in research; this is convenient because it’s also super fun. They lead every research project and are the driving forces generating ideas on what to work on and how to go about it. With my greater experience, I can initially point them in interesting directions and later serve as a sounding board as their research progresses, but the truly creative directions and insights come overwhelmingly from the junior researchers. In my work with Matt this has been true in spades: this project was entirely his brainchild, from initial conception to final completion.
This work was supported by the Natural Sciences and Engineering Research Council of Canada and the Canada Research Chairs program.
For more research from the Sivak Group see the Scholarly Impact of the Week: Whence your microbiome?
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