5. Protein Machines (1,117;8/31;pre-RL)

In the last chapter, we described a system that seemed almost paradoxical: a cell filled with molecules randomly colliding, binding, and separating—and yet somehow producing precise, coordinated behaviors. What makes this possible?

To begin to understand how the cell achieves anything at all, we need to dive even deeper and look more closely at the molecules that do most of the work by turning these countless random interactions into consistent, functional outcomes: proteins. Proteins are literally tiny molecular machines.

A typical human cell contains about a billion protein molecules, accounting for about 50% of the cell's dry weight (meaning what its weight would be if all water were removed). That’s much more than DNA, which accounts for only about 1-2%. While it is DNA that contains the cell’s long-term genetic information, proteins make up most of the machinery that acts on that information. In other words, DNA is comparatively passive; proteins are active job performers.

These billion proteins represent about 10,000 different kinds. The variety of jobs they perform is extraordinary. Some catalyze the chemical reactions that keep the cell running. Others transport cargo like vesicles and organelles from one part of the cell to another. Still others transmit signals between cells. Some switch genes on and off, determining both when and how much of a given protein will be made. Some form scaffolds and cables that give the cell its shape. Some cut DNA like scissors or chew up DNA like a molecular PacMan. Still others serve as antibodies that fight foreign invaders.

Realize, though, that proteins aren’t permanent fixtures. Some last only minutes or hours, while many have lifetimes measured in days. A relatively small number persist for months or even years. The cell is constantly renewing and adjusting much of its molecular machinery to maintain itself and meet its present needs.

Before delving further into protein function, let’s look at what a protein actually is. 

Proteins are polymers, a term for any long molecule made of repeating subunits. The subunits of polymers are generically called monomers. In proteins, the monomers are molecules called amino acids. Very simply, amino acids are the building blocks of proteins.

Every protein in the human body is a chain made out of 20 or so different kinds of amino acids . These 20 amino acids are all chemically different, but similar in that they’re all capable of attaching to each other in linear manner. On average, a human protein might be composed of 300 to 400 amino acids all lined up and connected. However, they can range in size from roughly 50 to thousands of amino acids long. 

By using this limited set of 20 amino acids as subcomponents, and mixing and matching liberally, the cell is able to create thousands of completely different kinds of protein machines. Imagine 20 different colored beads threaded onto a string. Each bead represents an amino acid. Any number of beads can be on the string. And the colors can be in any order.

We’ll call the order of amino acids in a particular protein its linear structure. The linear structure of a given protein could be represented by a simple list of its constituent amino acids in the correct order.

A newly made protein chain doesn’t stay linear for long, however. Within milliseconds, the chain twists, bends, and snaps into a precise three-dimensional shape.

This automatic "folding" occurs because different amino acids have different properties. Some are large; others are small. Some are hydrophilic (attracted to the surrounding water); others are hydrophobic (repelled by it). Some contain positively charged atoms; others contain negatively charged ones. As a result, they attract or repel each other like the positive and negative poles on a magnet.

No one directs protein folding. It arises from the forces generated on each amino acid by both their immediate surroundings and by other amino acids in the polymer. A protein’s final shape emerges from these myriad individual interactions.

We’ll call the protein’s folded form its folded structure. This is the functional three-dimensional form of the protein--the form capable of doing the kinds of jobs described earlier.

It’s easy to give the misleading impression that a folded protein is a rigid little object. It isn’t. Proteins are in constant motion. Their atoms jiggle, loops flex, domains pivot, and binding pockets open and close. A protein is less like a sold key than a tiny machine continually shifting among closely related shapes.

While different proteins do different jobs, most operate in a similar, or at least related, way: by binding, changing shape, and releasing. Binding often triggers the shape change--that "conformational" change we touched upon earlier--altering what the protein can do next. These changes generally occur in cycles: binding, shifting shae, carrying out a function, releasing, and returning to the original state. In this way, proteins operate not like static tools but like dynamic machines, cycling through different states as they interact with their surroundings.

Some protein machines go a step further: they consume chemical energy, usually from a molecule called ATP (adenosine triphosphate) that we’ll discuss in an upcoming chapter. That energy allows proteins to bias otherwise random molecular motion—to move along a filament, pull DNA through a channel, separate DNA strands, or force a complex from one state into another. Random collisions still bring molecules together, but energy consumption can make what happens afterward directional.

The complexity doesn’t stop with individual proteins. Folded proteins can themselves become components of larger machines called multi-protein complexes. A cell can therefore build a protein, fold it into a working unit, and then combine several such units into something with capabilities that none possessed alone.

For example, a multi-protein complex called the PCNA sliding clamp (that we’ll come to know well in the second part of this book) rides along a DNA double helix. It is assembled from three identical protein subunits arranged in a ring. Individually, none is a sliding clamp. Together, they create one.

Like the folding of individual proteins, the way proteins self-assemble into multi-protein complexes arises from local chemical interactions rather than any central design. In this case, it’s local, blind interactions between whole proteins rather than amino acids that result in a new, functional protein complex.

Proteins, then, are where random motion becomes directed activity. Proteins don’t plan or know what they are doing, but when they collide with the right partners in the right orientations, their shapes change in ways that produce consistent results. From these countless local interactions—binding, changing shape, releasing—coordinated cellular behavior emerges.

We’ll be introduced to many individual proteins and multi-protein complexes once we begin exploring genome replication. First, however, we need to get to know another molecule that is crucial to the cell.