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Molecular Machines Use Physics to Do Mechanical Work

The chemical reactions most of us learned about in high school or college involve exchanges of electrons as elements bounce about, crashing against each other. A chlorine atom has an extra electron in its outer orbital, and a sodium atom has room to accept it. Bang! The two molecules bind together into a unit of salt.

Molecular machines are fundamentally different, even though they also may exchange electrons at the atomic level. The cell’s machines are much larger, for one thing, constructed from elaborately folded polymers made up of building blocks that are themselves large molecules. More importantly, they have moving parts. The moving parts apply forces against other cell structures, achieving what we all learned as the mathematical definition of work: force times distance. Some forces are mechanical, as shown in our kinesin and ATP synthase animations, but some add electrical forces or aqueous forces (hydrophobic or hydrophilic). The best way to appreciate the variety of ways cells employ physical forces is to see them in action. Here are a few examples from recent literature.

The Folding Chamber

A molecular machine called the GroEL/ES system helps fold polypeptides into proteins. Many proteins can fold without help, but some seek a “chaperone” for assistance. GroEL/ES provides a private dressing room for these proteins. The “ES” part joins onto the barrel-shaped GroEL chamber, closing like a lid over the polypeptide inside. But that’s only where the fun begins. The machine actually pulls on stuck strands to keep them from mis-folding so that the polypeptide can get another start. Researchers publishing in Nature Communications described how this works for a protein named PepQ, a metalloprotease in E. coli.

Using cryo-electron microscopy, we show that the GroEL C-termini make physical contact with the PepQ folding intermediate and help retain it deep within the GroEL cavity, resulting in reduced compactness of the PepQ monomer. Our findings strongly support an active model of chaperonin-mediated protein folding, where partial unfolding of misfolded intermediates plays a key role. [Emphasis added.]

GroEL/ES can handle many different polypeptides besides PepQ, making it a multi-purpose folding chamber — pretty remarkable when you think about it. The researchers found “substantial unfolding” going on inside as the machine “actively alters” its substrate, “a process that relies in part on a direct, physical interaction” between the machine and its client. “Subsequent encapsulation of the partially unfolded folding PepQ monomer within the GroEL/ES chamber fundamentally alters the folding trajectory of the protein, resulting in a faster and more efficient search for the native state.” Does that bring to mind Doug Axe’s work on search space for proteins?

Dumpster Diving

That’s in a sense what researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP), says NewsWise, as they took a “deeper dive into cellular trash.” They wanted to learn more about the cell’s mechanism for recycling parts, known as autophagy (au-tof-a-jee), a process that involves segregating trash and taking it to a recycling plant called a lysosome. Knowing that problems with autophagy may be implicated with ageing, the researchers wanted to get a better “movie” of the process than snapshots have provided thus far:

Autophagy is a dynamic, multi-step process that starts with the formation of a double-membrane sac in the cell cytoplasm called the isolation membrane (IM). These structures engulf cellular material and debris, expanding in size to form vesicles called autophagosomes (APs). Finally, APs fuse with lysosomes to form autolysosomes (ALs) that digest and release the breakdown products for re-use, much like a recycling plant would repurpose incoming trash.

“A major challenge with understanding how aging impacts autophagy is that researchers have been capturing a dynamic process with static measurements,” explains Jessica Chang, Ph.D., a former postdoc in Hansen’s lab and first author of the study. “Autophagy is most commonly monitored by counting the number of APs, which really only provides a snapshot of the process — similar to how counting the number of garbage trucks on the street doesn’t tell you how much garbage is actually being recycled at the plant. And typically older organisms have an increased number of APs, but we don’t know exactly why.”

So they went to work, adding more frames to the “movie” by counting APs in different cell types in roundworms. They published their results in eLife, but it sounds like there’s a lot more to learn. What’s important is that here is another multi-purpose machine that goes beyond simple chemistry to do physical work in the cell, much like a garbage truck isolates all kinds of trash, sorts it, and tries to repurpose it.

Workers Inside a Platelet

Do you remember Michael Behe’s mind-boggling description of the blood-clotting cascade in his historic ID book Darwin’s Black Box? A new paper in Nature Scientific Reports digs a little deeper into this example of irreducible complexity, focusing just on one little aspect: shape changes in platelet cells when they spread out to form a clot.

The shape changes don’t “just happen” in a random way. They are controlled by molecular machines: specifically, dynein and myosin. These are “walking” motors that perform physical work. When a platelet becomes exposed to a break in the wall of a blood vessel, platelets accumulate at the break and start spreading out, due to the action of these motor proteins. In addition, dynamic protrusions called filopodia and surfaces called lamellipodia provide connection points for the growing clot, growing material into a kind of adhesive bandage.

The researchers found that thrombin, a multi-purpose enzyme mentioned in Behe’s book, plays a key role in triggering some of the physical shape changes in the platelet. Thrombin itself is a large, complex machine with four domains formed by other molecular machines. Look at all the physics going on as it switches on machines in a platelet:

Platelet activation, caused by agonists such as thrombin or by contact with the extracellular matrix, leads to platelet adhesion, aggregation, and coagulation. Activated platelets undergo shape changes, adhere, and spread at the site of injury to form a blood clot. We investigated the morphology and morphological dynamics of human platelets after complete spreading using fast scanning ion conductance microscopy (SICM). In contrast to unstimulated platelets, thrombin-stimulated platelets showed increased morphological activity after spreading and exhibited dynamic morphological changes in the form of wave-like movements of the lamellipodium and dynamic protrusions on the platelet body. The increase in morphological activity was dependent on thrombin concentration.

Spring-like Channel

Recently we looked at mechanotransduction in the sense of touch. One of the channels in the cell membrane that opens to let ions in turns out to act like a molecular spring. Phys.org includes an animated diagram of NOMPC (“nomp-see”) that works in a fly’s sense of touch and hearing. (See the top of this post.) The channel is made up of four units that each appear to respond to mechanical pressure much like a spring. Researchers from the University of California, publishing their findings in Nature, believe that as the spring is compressed, the channel opens to let the ions flow. This would make sense, because to respond to touch, channels must be directly pulled or twisted open by microscopic forces somehow, but more work will be needed to actually witness the physics in action.

Flagellum Escape Trick

We can’t forget the iconic bacterial flagellum in an article on molecular machines – another machine made famous by Michael Behe. Harvard flagellum investigator Howard Berg, mentioned by Scott Minnich in Unlocking the Mystery of Life, is still reviewing papers on flagella after all these years, and a new one in the Proceedings of the National Academy of Sciences has shown something quite unique and interesting: the escape trick. German researchers watched how a flagellated bacterium gets unstuck from a trap. It doesn’t just turn the motor into reverse. Here’s what it does:

It has long been established that flagella provide an efficient means of movement for bacteria in planktonic environments (free swimming) or across surfaces (swarming). However, rather little is known about bacterial motility in structured environments. In this study, we demonstrate that polarly flagellated bacteria can exploit a polymorphic instability of the flagellar filament for a third type of flagella-mediated movement in which the flagellum wraps around the cell body and the cells back out from narrow passages in a screw-like motion.

We’ll stop here, because it’s hard to top that!

Understanding molecular machines is the biology of the future. Here we have seen five examples of complex machines, composed of precisely sequenced amino acids encoded by DNA, that use physical forces to perform mechanical work. We can relate to the physical principles (springs, screws, and controlled pushes and pulls) in our own experience with machines, leading to a natural inference of intelligent design. But to find these things at work in living cells at the scale of nanometers — that’s something else again, and quite exciting.