Computers Hack Resistant AIDS Virus--HIV Naked Before Researchers

Computers are finding many uses in modern scientific research. Newer, more powerful computers are being programmed to simulate complex proteins and other large molecules and complex systems. One of the proteins being simulated is the HIV protease, a molecule vital to HIV replication inside the cell. Protease inhibitors are commonly used to treat HIV infections, but some HIV strains have grown resistant to protease inhibitors. In order to understand this resistance, researchers have used computer simulations to mimic the particular HIV proteases that are resistant--so that they can find a weakness to target.

For more than a year, researchers watched patiently as a few computer-simulated HIV protease molecules squirmed into more than 15,000 slightly different shapes. In real time, this contortion takes only a fraction of a second. In the end, however, this suspended animation paid off, as the simulations uncovered a potential new drug target to fight drug-resistant AIDS.

Howard Hughes Medical Institute (HHMI) scientists made the discovery while studying how one rare strain of HIV can evade a commonly prescribed class of drugs used to treat the virus that causes AIDS. The strain of HIV contained mutations that are often seen after failure of treatment with protease inhibitors, drugs that block the action of the enzyme protease and prevent the virus from making mature, infective copies of itself. When protease inhibitors fail -- as they often do with a fast-mutating virus like HIV -- new drug targets become vital.

"Recognizing these variations in conformation -- the three-dimensional arrangement of the amino acids that make up a protein -- is the first step in identifying a new drug target," said Alex Perryman, first author of the study published early online in the journal Biopolymers on February 28, 2006.

....Perryman used a computer simulation program called AMBER that performs several different types of calculations. The x-ray crystal structure of the molecule is used as the input, and the various motions and shapes sampled are governed by Newtonian physics, the electric forces among atoms, the complementarity or clash of the different shapes that the enzyme takes, and penalties or bonuses for creating or relieving geometric strain.

The scientists depict the protease enzyme in a brightly colored cartoon, with features that resemble a fat cat face. From the front or the back, the identical halves of the enzyme have an ear and cheek protrusion on each side. (See illustration.) Frayed whiskers even appear to sprout from the bottom. The similarity to a face ends at the top of the molecule, where two flaps open to reveal a cavity. That is where enzymes and other proteins are cleaved into the parts necessary to assemble infectious virus particles. Structural studies of this cavity helped scientists find the original protease inhibitors. Other scientists are trying to design drugs to bind to the whiskers and or to lock down the flaps by binding to their top.

Perryman's first results, which were published in the April 1, 2004, issue of Protein Science, showed that the mechanism of drug resistance seemed to involve the motion of the flaps. More specifically, the double-mutant virus displayed larger flap motions, especially at the tips. These larger movements seem to make it more difficult for the current drugs to function, since they must force the flaps to close and remain closed in order to prevent the enzyme from working. It probably takes more energy for the drugs to close the more mobile flaps of the mutant.

Perryman and his colleagues also observed that the flaps opened in a seesaw motion on each side, pinching the "cheek and "ear" together. That observation suggested to them that a small molecule might be able to wedge between the ear and cheek, blocking the flap opening.

"Some drugs act by binding to the active site of a target molecule, such as the site that an enzyme normally uses to catalyze reactions," McCammon said. "But increasingly, scientists are finding that other binding sites can be important. For HIV/AIDS, an important class of drugs called non-nucleotide inhibitors for reverse transcriptase typically bind at such alternate sites."

Once Perryman had a hypothesis to test in a second round of simulations -- the proposed mechanics of the protease enzyme's nanomachinery--he used artificial restraints in the computer program to block the flaps from opening by expanding the gap between "ear" and "cheek." A new type of drug that binds there and controls flap motion could enhance the ability of the current protease inhibitors to bind to the active site, or it could offer a new way of inhibiting protease activity from afar by itself, Perryman suggested.

This type of computer simulation can certainly be used to locate a wide range of molecular targets. Read the entire report, including other potential target molecules being simulated, here.

Conventional von Neumann computers are actually pretty stupid. But they are very fast calculators, and can model some complex systems. Computers are getting faster all the time, and more sophisticated designs incorporating massive parallelism and neural net architectures can do some impressive things. Expect a lot more in the future.