Figure 1: A molecular model showing the rotor ring component of ATP synthase. In a molecular dynamics study, RIKEN researchers have discovered the rotational mechanism for F1-ATPase. © LAGUNA DESIGN/SCIENCE PHOTO LIBRARY
The way a key cellular motor works at an atomic level has been uncovered by simulations conducted by RIKEN biophysicists1. This finding provides important insights into how mechanical force is generated in cells.
Many of the processes in our cells are powered by a critical energy-storing molecule known as adenosine triphosphate (ATP). A typical human cell uses millions of ATP molecules a second to generate the energy it needs to function.
"ATP is an essential molecule in cells," says Yuji Sugita of the RIKEN Theoretical Molecular Science Laboratory. "Many motor proteins use the hydrolysis of ATP to convert chemical energy into mechanical work."
ATP is produced by an enzyme called ATPase, which consists of two molecular motors, Fo and F1, that rotate in opposite directions. When the handle of Fo is 'cranked' by protons, it enables F1 to churn out ATP molecules.
Now, Sugita and his co-workers have investigated the rotation of F1-ATPase by performing detailed molecular simulations using the supercomputer Fugaku at RIKEN.
"F1-ATPase is one of the most interesting molecular motors and has been the best studied structurally and functionally," notes Sugita. "There's a long history of research into it."
However, due to computing limitations, previous molecular simulations fell short of modeling F1-ATPase in its full glory. Instead, they had to resort to either using course-grained models or include an external force to drive the rotation of F1-ATPase.
Sugita and his team were able to overcome this limitation by using Fugaku.
"The system we modeled is highly complex, consisting of more than half a million atoms, and we produced 64 intermediate structures of this system," says Sugita. "Fugaku allowed us to perform 64 molecular dynamics simulations in parallel, which were impossible in previous studies."
F1-ATPase has a rotary element that rotates through 120 degrees relative to a stationary component. This rotation occurs in two steps: one of 80 degrees and the other of 40 degrees. The team analyzed the 80-degree step in this study.
They discovered a new mechanism for this rotation, finding that it is driven by distortion of the stationary section of F1-ATPase followed by a pushing force acting on the rotating section.
"We can explain the 80-degree rotation in terms of this distortion-push mechanism, which had not been considered before," says Sugita.
The team's rotational mechanism is consistent with experimental observations of F1-ATPase, including molecular structures obtained using cryo-electron microscopy and single-molecule spectroscopy.
The team now intends to apply the same approach to the second, 40-degree rotation of F1-ATPase.
