A new study in the Biophysical Journal describes the work of scientists who have created a series of compounds that could serve as an alternative synthetic energy source for myosin.
The “energy currency” of life
The marriage of biology and engineering makes it possible to design or redesign biological molecules and complex systems that do not naturally exist in the world – whose applications are unprecedented.
The latest addition to the growing synthetic biology research literature is a collaborative study by Woodward and colleagues, published in the Biophysical Journal. Scientists have combined chemistry, kinesiology and computer modeling to discover an alternative energy source to adenosine triphosphate (ATP) for muscles.
The research grew out of a shared journey at the University of Massachusetts Amherst. Ned Debold and chemist Dhandapani Venkataraman (DV) spent their bus trip discussing a mutual fascination with energy conversion – for Debold, that interest focused on muscle tissue, while Venkataraman reflected on solar cells.
Debold’s team had explored an alternative energy source to ATP, the energy-carrying molecule that powers muscle contraction and movement and is considered by many to be the “energy currency” of life. In the body, muscle shortening occurs when myosin heads bind to a protein known as actin and pull actin inward. To provide the energy for this process, ATP is hydrolyzed to adenosine diphosphate, releasing an inorganic phosphate molecule and energy.
If ATP is the energy currency of life, why do we need an alternative source?
Myosin with azoTP and ATP in its active site. Credit: UMass Amherst / Debold Lab.
A new compound to boost or inhibit myosin
There are several human diseases that involve the musculoskeletal system, such as cerebral palsy, multiple sclerosis, chronic heart failure, and amyotrophic lateral sclerosis. Some of these conditions involve muscle spasms, involuntary movements, or muscle stiffness and weakness. As the treatment options are somewhat limited, they can prove to be very debilitating and negatively impact an individual’s quality of life. The ability to create a new compound that could inhibit or improve myosin function could offer new treatment options for patients.
In one Press release, Venkataraman notes that the typical approach to researching a new compound is to systematically test a series of compounds until you find one that seems worth following, comparable to finding a needle in a haystack: “At one point I suggested to Ned, ‘Why don’t we build the needle ourselves instead? “It got us started on this interesting project that brought together people who otherwise would never work together.”
Venkatarman would create the synthetic molecules and Debold would test their effects on myosin. But it soon became clear that a bridge was needed between the two – someone to model the interactions in a computer – so chemist Jianhan Chen joined the research team.
“We did computer modeling because experimentally, it is difficult to know how myosin could use the molecules synthesized by DV. We can use computer simulation to provide a detailed picture at the molecular level to understand why these compounds might have certain effects. This may provide insight not only into how myosin interacts with the current set of compounds, but also a roadmap for DV to use to design new compounds that are even more effective at altering myosin function, ”he said. said Chen in a Press release.
To create the synthetic molecules, Venkataraman turned to positional isomerism, in which the carbon skeleton of a molecule remains unchanged, but the groups are effectively displaced on that skeleton. In the article, it is described by the team as “a simple and powerful tool to control the molecular motor of muscle, myosin”.
Three isomers of a new ATP substitute
The results published in the Biophysical Journal show that scientists were able to synthesize three isomers of a new ATP surrogate: “Using three isomers of a synthetic non-nucleoside triphosphate, we demonstrate that the strength and movement-generating ability of myosin can be dramatically increased. modified at the level of the whole and the single molecule. by correlating our experimental results with calculus, we show that each isomer exerts intrinsic control by affecting distinct stages in the mechanochemical cycle of myosin, ”state the authors in the article.
Venkataraman added in a Press release: “My lab had never made such types of compounds before, we had to learn new chemistry; my student Eric Ostrander worked on the synthesis.
Researchers are demonstrating what appears to be a simplistic but powerful approach to taking control of molecular motor function, but it’s still just the start. Advancing the research, the team will endeavor to map various points in the biochemical cycle of myosin, a concept that is still somewhat elusive to scientists.
“In the field of muscle research, we still don’t fully understand how myosin converts the energy gain from the food we eat into mechanical work. This is a question that is central to understanding muscle contraction. By supplying carefully designed alternative energy sources with myosin, we can understand how this complex molecular engine works. And along the way, we’ll likely reveal new targets and approaches to treat a host of muscle-related diseases, ”said Debold.
Woodward et al. (2020). The positional isomers of a non-nucleoside substrate affect the function of myosin differently. Biophysical Journal. DOI: https://doi.org/10.1016/j.bpj.2020.06.024.