Myosin motors give cells their muscle

Rice, UCSD simulations define window of opportunity for protein to flex actin networks

To serve out useful lives, cells have to flex a little muscle. How that happens is now less of a mystery, based on simulations by researchers at Rice University and the University of California at San Diego (UCSD).

Peter Wolynes

Through computer models, the team led by Rice chemist Peter Wolynes  determined that myosin, a molecular “motor” protein fueled by adenosine triphosphate (ATP), takes advantage of a very small window of opportunity to manipulate actin  filaments in the gossamer network of protein strands that are part of every living cell.

Not enough myosin leaves the micro-muscle flabby. Too much and it becomes muscle-bound. But just the right amount lets it manipulate the network, which is important to a cell’s ability to transport materials and to divide.

The results were reported in the online Proceedings of the National Academy of Sciences.

Actin filaments are part of the cytoskeleton, the protein scaffold responsible for controlling the environment within a cell. Wolynes and his graduate student at UCSD, Shenshen Wang, looked at how the collective action of myosin motors organizes actin filaments into structures that can contract, a function that plays roles in healing and gastric processes, among others.

“We’re trying to build the concepts we need to think about the structure of the cell,” said Wolynes, the Welch Foundation Professor of Science and a professor of chemistry, who moved from UCSD to Rice last year. “A lot of people make pictures of what’s inside a cell, and if you ask them the most basic question – ‘Is that picture the same from cell to cell?’ – they usually say, ‘No.'”

Wolynes, whose primary field of study involves the flow of energy across microscopic “landscapes,” particularly those inhabited by proteins, wondered how and why the elements inside a cell are prompted into motion.

Wolynes said he and Wang found the number of myosin motors that connect two actin filaments like rungs on a ladder are critical to the structure’s behavior. “The fibers are connected by motor proteins that themselves form itty-bitty fibers,” Wolynes said. “Because they pull the actin in a correlated way, you get something that has the possibility of contracting like a muscle, but on the microscale.

“What was surprising was that there’s a window of connectivity,” he said. In the simulation, if there were too few myosin connections between filaments, the actin wouldn’t contract. “It would be like a flabby muscle,” he said. Too many connections would make the fibers essentially muscle-bound. “We found we needed to have a certain amount of critical connectivity before the thing could contract as a whole.”

Contraction is as important on the microscopic level as it is on the macro level, where the concepts translate into the movement of muscles. But for this study, Wolynes and Wang modeled only two components in the process that takes place inside cells to see if their results supported what had been observed in vitro by other labs; they did

Their simulated network was designed as a random cat’s cradle, rather than a linear collection of filaments. This allowed them to see what would happen when myosin proteins delivered “kicks” via elastic bonds to the actin proteins on either side.

These kicks, Wolynes explained, happen when myosin does its job by absorbing and breaking apart ATP. Myosin has two folded configurations, and upon digesting ATP, it reconfigures itself from one structure to the other. That process is a universe of research unto itself, “but in this model, the whole is subsumed into one step,” Wolynes said. “It saddens me, I suppose, to take all that beautiful process and simply call it a ‘kick.'”

The energy released when that refolding takes place determines the strength of the kick, which begins a mini tug-of-war between the connected nodes on separate strands of actin. When enough kicks take place in a well-connected network, the micro-muscle is triggered to contract, Wolynes said.

“Our theory is very simple, as it has only the actin and myosin,” Wolynes said. “The reality is there is a zoo of other proteins (as well as other hydro- and thermodynamic forces) involved in setting and controlling the connectivity of the tissues. In some sense, the living system has evolved to figure these physics out; we’re just looking at one little part.

“This is a remarkably rich system,” he said. “We still don’t know much about everything that goes on inside a cell, but we can explore this richness right now.”

The research was funded by the Center for Theoretical Biological Physics, a collaboration between researchers at Rice and UCSD supported by the National Science Foundation.

A model schematic shows links between strands of actin that can be "kicked" into contracting by minifilaments of myosin, a "motor" protein that digests ATP. Illustration courtesy Shenshen Wang/UCSD