You've heard it said: Amino acids are the building blocks of life. More literally, amino acids are the building blocks of proteins -- and proteins are the walls, doors, monorails and kitchen sinks of life. A protein is made from a strand of amino acids strung together like the various figures on a charm bracelet. Each amino acid has an identity, properties and charm all its own. Some amino acids are bulky or rigid while others are small or flexible. Some amino acids are electrically charged and others are neutral. Some amino acids prefer to be in water while others shun water and seek to bundle together or imbed themselves in globs of fat.
With all of these various and competing properties, it's not surprising that an amino acid in a strand can interact with its neighbors, perhaps pushing one away which causes the string to bend. But it can also interact with amino acids far along the string that come into the neighborhood when the protein string curls back on itself. To further complicate matters, an amino acid on one protein can hook up with an amino acid on a completely separate protein, resulting in multi-protein complexes.
Twist and Shout
All proteins start out as a simple string of amino acids but then, as the string starts to flop around and interact with itself, it begins to fold into clumps or twist into braids or take on any number of shapes. The water-hating amino acids tend to clump together and push their water-loving neighbors away. Amino acids hundreds of positions apart on the protein string find themselves married together in its folded state. These kinds of interactions help give the protein its working form. To further differentiate the behavior of a protein, some amino acids might attract and festoon themselves with various sugars or bits of energized phosphorous molecules. With only 20 different amino acids -- each with different properties, all interacting with each other -- proteins can take on an amazing range of diversity in shape and function.
Proteins are all about function. Some proteins have structural roles, acting like girders, belts, wires, tracks and zippers. Most every protein is able to hook up to other molecules in some way, with some acting specifically as connectors or adapters, similar to fish hooks, sockets or Velcro. Other proteins act like doorbells or mail slots that relay signals from one side of a cell to the other. Enzymes are specialized proteins that behave like machines and have moving parts such as grippers and cutters. Enzymes perform their work on various chemicals or other proteins called substrates. The enzyme stabilizes and speeds up the modification of substrates by holding them steady while highly specific operations are performed.
Proteins can do every imaginable (and many as yet unimagined) job in a living organism. Proteins can be described by their characteristic sequences of amino acids, by their three-dimensional structures or by the functions they perform. Just to complicate things, two proteins with very similar activity or structures may have completely different sequences. Not every protein has to fold up into its perfect final form; some do their work by just flopping around. Others need to be embedded into a cell's membrane before they truly come alive and do their job. Some proteins only exist to guide other proteins as they fold themselves into useful shapes. Proteins that don't fold themselves correctly can be a source of disease. Broken or defective proteins in a cell are usually quickly collected, taken apart and recycled by -- what else? -- other proteins. Scientists are using powerful computers to try to predict the behavior of strings of amino acids when they start to clump together and curl up, but the problem is so complex, they have only begun to scratch the surface.
HIV Is Made of Proteins
The HIV protease enzyme is made of a protein with two main moving parts hinged by a flexible sequence of amino acids. The job of the HIV protease is to hold onto other HIV precursor proteins and cut them apart between specific amino acids pairs. After the HIV substrate proteins have been cut, they are free to fold themselves into the various structural bits and machinery that make up a new HIV virus particle. These new proteins may include parts of the inner and outer shell of HIV as well as the HIV-enzymes reverse transcriptase, integrase and protease itself. If HIV protease can be prevented from cutting the HIV substrate protein in the right places, the virus can't replicate.
Of course, this is what protease inhibitors (PI) are designed to do. These drugs are little molecules that imitate the amino acid sequence of the HIV substrate protein where protease is supposed to make it's cut. But instead of cutting, the protease gets stuck on the decoy molecule and everything stops. These drugs work fine as long as the protease enzyme is made from its standard, out of the box, string of amino acids. But if a few of the amino acids have been changed, or if some amino acids are cut out or different ones added, the protease starts behaving differently. Maybe the altered protease starts to grab the drug molecule but then drops it again before picking up a real HIV substrate and cutting it. The altered protease is still not working at nearly its normal speed but it is managing to pump out a small amount of fresh virus. This process can just limp along until one day a new version of protease shows up with another switched amino acid that now lets the altered protease regain its old familiar efficiency by zeroing in on the HIV substrate while ignoring those pesky decoy drugs completely.
These are scenarios for drug activity and drug resistance. A few key substitutions of the amino acids in the enzyme can let HIV protease get on with its job despite the drugs. The enzyme may be a little out of whack, but it can still do its job; it has compensated. It's like someone who limps after hurting her foot: She may be slower, but she's still getting around. The enzymes may limp a bit, but they learn to get by.
The Genius of Genes
Proteins are the products of genes. Proteins are active, messy things that go out to interact with the rough-and-tumble world and do things. They can have a limited life span and often get chopped up and recycled after they have done their jobs. But new proteins are always waiting to be made. The master recipe for assembling the string of amino acids that makes up a protein is stored in a completely different type of chemical structure called genetic material. Genetic material (made from DNA or RNA) is also arranged in the form of a string, but one made from nucleotide molecules instead of amino acid molecules. While there are 20 different types of amino acids that make up proteins, genes basically use only four different kinds of nucleotides.
A string of three nucleotides forms a code: Every set of three nucleotides in a gene represents one amino acid. A sequence of these nucleotide trios corresponds to a sequence of amino acids in a protein. Although there are only four nucleotides to work with, as a set of three (4 times 4 times 4) enough combinations can be made to code for up to 64 amino acids. Fortunately, we only need 20, so most amino acids have more than one set of nucleotide codes.
The Seeds of Resistance
There is a set of machinery that is responsible for reading a copied piece of genetic code and assembling the right amino acids in the right order to make proteins. This process is called translation and the translating machinery builds the protein that it's told to build by the genetic material. There is a different set of cellular and viral machinery that is responsible for storing, retrieving and making copies of the genetic material. This is where trouble creeps in.
If the machinery responsible for copying and storing the HIV gene skips one of the nucleotides or reads it wrong, several things could happen. Since the three-letter code for the amino acid has been changed, it may now code for a different amino acid, the same amino acid (using one of the alternate codes) or it may code for nothing at all. The translating machinery doesn't care; it just goes to work on what it is given. As the protein is assembled, it may stop short or it may become a useless mess of a mutant. But sometimes, the substituted amino acid will continue to work just fine. In some cases this is because the change does not matter, but in special, rare cases that result in drug resistance, the changed amino acid may actually help the enzyme to ignore the drug molecules while continuing to perform it's duties. This is a drug resistant mutant and if it is successful, it will thrive.