The tiny engines that power life itself

Biologists studying living cells are realising the power of the sub-microscopic machines that run them. Simon Hadlington asks what can engineers learn from nature's highly efficient motors

Neither Justin Molloy nor Richard Berry cuts a likely figure as a motor mechanic. They don't wear greasy overalls or wield monkey wrenches or stand over the open bonnet of your car shaking their heads and tutting ominously. Justin Molloy's expertise at York University is in what might broadly be termed chemical motors – ones that take chemical energy as their fuel and convert it into mechanical force. Richard Berry at Oxford is concerned with electrical motors.

The motors these two men spend their days taking apart, reassembling, tweaking and tuning are far from conventional. They are small – very small. Many millions would fit into the full stop at the end of this sentence. They are molecular motors. Recent advances in biology are demonstrating that many of the fundamental processes of life are driven by tiny, sub-microscopic engines – assemblies of protein molecules that can exert a mechanical force in a specific direction. Bacteria, for example, have corkscrew-shaped propellers rigged up to rotary molecular motors to move them through their environment in search of food.

The study of these motors is having a wider impact on the way that natural systems are themselves perceived. "Over the last few decades it has started to become clear that pretty much everything that is going on in living organisms is mechanistic," Dr Berry says. "Some sort of tiny machine is performing a specific function in a defined and controlled way. It is a whole new frontier, which is just beginning to come together. Much of what we had previously called biochemistry is in fact engineering at a tiny scale."

Every human cell is packed with motors: to pull chromosomes apart and pinch cells in the middle to make them divide; to move substances through the cell for export; to haul substances into the cell. Motorised systems shuttle sacs of nerve transmitter up and down nerve cells from your spinal cord to the tips of your fingers. Molecular motors power the thrashing motion of a sperm cell's tail, and cause muscles to contract.

The question that scientists such as Dr Molloy and Dr Berry are asking is: how do molecular motors work? How is directed mechanical force produced on this vanishingly tiny scale?

Broadly, molecular motors fall into two categories: chemical motors, which extract the energy from a fuel molecule called ATP to create force; and electrical motors, which are rotary and which are driven by a flow of ions across cell membranes.

In the Clarendon laboratory at Oxford University, Dr Berry is studying fundamental aspects of the electrical rotary motor that propels bacteria. Here, a long filament – the propeller – is attached to a ring-shaped rotor, made of protein segments, in the bacterium's cell membrane. Around the rotor there is a larger ring of protein. This corresponds to the stator – the part of the motor that remains fixed but somehow exerts a force on the inner rotor to make it spin several hundred times a second.

It is known that these rotary motors are driven by the flow of electrically charged atoms, or ions, from outside the cell membrane to the inside – in other words, a voltage difference. Usually these ions are protons – hydrogen ions – although they can be others, such as sodium ions. What is not understood is precisely how the stator pushes the rotor and how the flow of ions is coupled to this activity.

"There are a number of models, some more plausible than others," says Dr Berry. One idea is that as the ion passes through the stator protein it attaches itself to a specific site, causing protruding portions of the structure to grab hold of the rotor then change shape, inflicting a force on the rotor and making it revolve. The ion then continues on its journey into the cell, allowing the protein to release the rotor and return to its original configuration – a bit like someone standing still and pushing a playground roundabout.

Another idea has been called the "proton turbine" model. Here protons whizz through special channels in the stator, passing close to the rotor but not actually coming into contact with it. The rotor itself has an electric charge on its surface, dictated by the way the protein molecules are constructed. Because proteins can have highly organised shapes it is conceivable that the charge adopts a particular geometry – a helical pattern, for example, like the thread on a screw. As the protons pass nearby there is an electrostatic attraction and the charge on the rotor's surface "follows" the proton, causing the rotor to spin.

One way of narrowing down the possibilities is to measure accurately the forces generated by these motors and compare the experimental results with those predicted by the models. Dr Berry is using laser-based techniques to do this. Bacteria can be stuck to a glass slide and small polystyrene beads attached to their propellers. It is possible to measure the rotation of the beads by observing how they deflect tightly focused laser beams. "In this way we can measure the torque of the motor and can see how this depends on the voltage that is driving the system," Dr Berry says. "By making measurements like this we can infer how the engine might or might not be driven."

At the University of York, Dr Molloy is carrying out similarly detailed experiments on the molecular motors that use chemical fuel. These motors are also made from proteins. The family of proteins Dr Molloy studies are called the myosins, the best studied of which is the myosin protein that drives muscle contraction. However, we now know that there is a diverse collection of these myosins and that in most human cells there are 10 or 15 different types all working away, each with its own specific function.

Myosin exerts force by taking a single molecule of ATP, breaking it down, and in the process giving a minute mechanical "kick". The molecule is shaped like an extended ellipse, about five nanometres across and 25 nanometres long (a nanometre being a millionth of a millimetre and the unit of length used to describe structures at the molecular scale).

This elongation is crucial to the way it works. "The fuel molecule, ATP, docks into a binding site on the motor," Dr Molloy says. "Here it is split and the two products are released one after the other." As the products leave the protein they somehow induce it to change shape. A small movement at the site where the ATP is split is – by virtue of the length of the motor – geared up into a much larger kick at the other end of the molecule. This is the "working stroke" of the motor. If one end of the motor is anchored, the system acts like a swinging lever and can be harnessed to do useful work.

In muscle, myosin molecules are aggregated into filaments with the motor heads protruding. These lie adjacent to another filamentous protein called actin. Just before the individual myosin motors undergo their working strokes they attach to the actin filament, releasing it after the "kick" before reattaching to repeat the cycle. "It is similar to a rowing action," says Dr Molloy. "Like oars in water, the myosin pulls against the actin and is then removed for the recovery stroke." Multiply this several billion times and you have a flexing bicep resulting from actin and myosin filaments sliding over one another.

Dr Molloy's team at York is interested in the way in which the chemical energy of ATP is converted into mechanical work. The team extracts and purifies different types of myosin and experiments with single molecules of the protein. By using sophisticated laser-based techniques the team was the first to measure the force and movement produced by a single myosin motor unit.

Unsurprisingly, both the rotary motors and the "kicking" motors are exciting the interests of nanotechnologists – scientists attempting to build molecular-scale machines and devices.

"Myosin is truly a molecular machine," says Dr Molloy. "One molecule of motor processes one molecule of fuel to produce a single mechanical kick. Engineers and physicists looking to develop nano-scale machines would dearly like to make them operate in this way."

Dr Berry adds: "If we want to build machines on this scale out of silicon or DNA we need to know the fundamental principles of how they work, and the obvious place to look is nature, which does it so efficiently and elegantly."