Back when you were first exposed to chemistry in school, you probably learned about the equations describing chemical reactions; for example, the reaction between hydrochloric acid and sodium hydroxide:
HCl + NaOH -> H2O + NaCl
giving water and sodium chloride (salt) as reaction products. Students at that point can be pardoned for thinking that figuring out how chemistry works is largely a matter of getting these equations to balance. When one gets to reactions involving more complicated compounds, and especially more complicated biological molecules, knowing how many of what sort of atoms are present is just a small first step. Many biological molecules have functions that are intimately related to their shapes. Most readers, I’m sure, will have seen images of the double helix of DNA; that shape is central to the way that DNA works as a recording mechanism for genetic information, and it took a good while to figure it out.
Proteins, which are long chains of amino acids, also have shapes related to their functions, and vice versa. Enzymes, which are a particular class of proteins that act as catalysts, are necessary for almost all in-cell reactions to be carried on at a rate sufficient to support life. Because they are typically large molecules, they can potentially exist in a variety of shapes; generally, the most stable form (which has the lowest energy) is the biologically active form.
Researchers investigating retroviral infections, like HIV, have been interested for some time in an enzyme called M-PMV retroviral protease, which is found in a retrovirus that causes an HIV-like disease in monkeys and apes. (The virus itself is called Mason-Pfizer Monkey Virus.) The M-PMV enzyme is known to be essential to retroviral growth, and its sequence of amino acids has been known for some time. But, until quite recently, the shape of the molecule, and the crystal structure that it implied, were unknown. Typically, biochemists attempt to use computer-based minimization techniques to search for the lowest-energy, stable shape; however, because of the very large number of possible configurations, and the resulting very large search space, this can be a difficult task. In the case of the M-PMV retroviral protease enzyme, the search has been going on for years.
The BBC has now reported that the structure has been found, based on the work of players in an on-line protein-folding game, FoldIt, and scientists at the University of Washington. The gamers were given a starting set of molecular configurations; their objective was to try to find the lowest energy shape.
Following simple rules, gamers playing Foldit had to turn and flip a digital 3D model of the enzyme on their computer screens, to try out all folding combinations that were possible.
They eventually obtained the optimum one – the state that needed the lowest energy to maintain.
The game attempts to take advantage of people’s pattern recognition and spatial reasoning abilities, combining them with the machine’s ability to rapidly compute the implications of a new molecular shape. The research was published in the journal Nature Structural & Molecular Biology [abstract]; the full article can be downloaded here [PDF].
This potentially is an important new tool for understanding the biochemistry of these retroviruses. Because the action of protease enzymes is essential to the retroviruses’ life cycle, many existing anti-HIV drugs, such as ritonavir [Norvir] and nelfinavir [Viracept], are protease inhibitors. Gaining a better understanding of the structure of these enzymes might provide real help to drug developers.
Many thanks to Pat for bringing this item to my attention! The New Scientist also has an article on this research.