So What Does Dan Actually Do?

"What do you study, Dan?" This is a surprisingly difficult question with several answers, depending on who is asking.

To another scientist of the right kind, I can give the reasonably detailed answer, "I study protein folding kinetics by molecular dynamics simulations, followed by Bayesian analysis of states and rates. The general idea is to criticize and improve master equation models of microscopic protein dynamics."

For some other scientists, "I study protein folding kinetics using computer simulation." Short, sweet.

For non-scientists? This is trickier, and I'm a bit ashamed not to have a short answer prepared. However, the short answer is difficult; look at the "other scientists" response, in particular. Parts of that sentence parse for reasonably intelligent laiety, like "computer simulation." I calculate stuff (generally stuff that's either too hard to measure or too small or fast to see, but that's part of a more detailed answer). Much harder is explaining what "protein folding" is. "Kinetics" is also probably tricky, but it's just a technical word for the measurement of how and how fast something happens. "Protein folding kinetics" is studying how and how fast protein folding happens.

I imagine people think of folding sliced ham in half when they hear "protein folding," but the protein in protein folding doesn't refer to dietary protein like a slice of ham, but to biochemical protein. This is much like "water": when most people (including scientists) refer to water, they mean the liquid. "Water" sometimes means the molecule, water, H₂O, meaning two hydrogen atoms attached by chemical bonds to an oxygen atom.

Proteins are molecules, too, of a class called macromolecules because they're huge compared to ordinary molecules like water. Other macromolecules include lipids--that is, fats, which actually aren't that big--and nucleic acids like RNA, which is about as big as a protein, and DNA which is huge compared to proteins and RNA.

In technical language, proteins are linear polymers of amino acids. This means that proteins are bigger molecules made from sticking small amino acid molecules together, end to end, by chemical bonds. The amino acids are a class of molecules, of which twenty or so are used in biology, with one end (the "amino" end, made of nitrogen, with a name not coincidentally reminiscent of the solvent, ammonia) which can stick, chemically, to the other end (the "acid" end). With dozens or hundreds of these molecules stuck together, end on end, one gets a protein macromolecule, which topologically speaking is a long chain of amino acids, like a string.

Proteins perform lots of different tasks for the cell, with one type of protein doing about one specific task. For instance, hemoglobin is a protein that carries oxygen in the blood; IDH is a less famous protein that cleaves one molecule, isocitrate, into two, carbon dioxide and alpha-ketoglutarate.

However, a protein in the form of a string of amino acids cannot do its job. Hemoglobin can't carry oxygen in string form, and IDH can't cleave isocitrate. In order to perform its function, the protein string needs to fold into a specific shape. Luckily, the information for folding into the right shape is encoded in the string of amino acids, some of which are oily, and avoid water, and some of which are hydrophilic, or "water-loving," but better called water soluble. However, remember that the amino acids are stuck together into a chain; the information of the proper fold is encoded in the different arrangements of the chain so as to hide oily amino acids from water, and to get water soluble amino acids into contact with water. The proper folded conformation is the most likely conformation that does the best job getting all of the right amino acids away from or in water, according to which amino acids are in the chain.

The particular chain for a protein is unique; hemoglobin is different from myoglobin which is different from IDH. Therefore, the fold is different. One way to study protein folding, known as structure prediction, is to try to guess from the sequence of amino acids what the final structure will be. On the other hand, I study protein folding kinetics, which is how the protein gets to the folded state in the first place.

Protein folding is impossible, with state-of-the-art technology, to observe directly in the lab, so I and my coworkers (and others around the world) use computers to model how the atoms in the protein macromolecule move around. The atoms have velocities, and they exert forces on one another. For instance, positively charged atoms attract negatively charged atoms, according to the ordinary rules of electrostatics. Since they exert forces, the atoms accelerate or change velocity, and they zoom around. However, the atoms are chemically bound in certain arrangements, they don't zoom around too much, so really all the protien chain can do is flop around in different arrangements.

Spaghetti illustrates this quite nicely. A pot of noodles thrown on the floor shows lots of pasta (protein chains) which flop in different ways. The forces that a protein chain exerts on itself makes the protein move between different conformations. Some of these conformations are (or are very close to) the proper, functional conformation of a protein.

With molecular simulation, we calculate the next conformation, in time, that a protein molecule will adopt, from its characteristics at the current conformation. Thus, the protein chain moves from conformation to conformation, and eventually folds into the correct, functional shape.

I study how a protein moves between the different shapes it can adopt, and, more interestingly, how quickly it can change from shape to shape, using a computer. The final piece is to state why a person would want to know about this: as might be guessed, knowledge about how proteins fold is one of the keys to understanding their many functions.