The growing stockpile of protein data has, in the last few years, enabled development of smarter computer algorithms that are giving scientists the power to redesign proteins virtually and with greater speed and accuracy. These “computational design” algorithms are able to scan through truly staggering numbers of potential sequence and structure variations — far more than would be possible in a lab — and serve up the best designs. “I think that combinatorial biology has more successes to its name than pure computational design,” says Brian Kuhlman, an associate professor of biochemistry at the University of North Carolina at Chapel Hill, “but there are some things that you would be very hard-pressed to do with only combinatorial biology, such as design an entirely new protein structure.” Kuhlman was a postdoctoral fellow in David Baker’s lab at the University of Washington, where the first computational design of a protein not found in nature was achieved.

The Baker Lab used Rosetta, free software initially developed to predict the structure of existing proteins. But since 2005, the lab has been using Rosetta to identify amino acid sequences that provide the best fit for their target structure, while simultaneously introducing tiny tweaks that make a resulting protein as stable and likely to fold properly as possible. “One of the most interesting things that has helped the field is the realization that tools that are developed for protein-structure prediction are equally useful for protein design,” says Kuhlman.

Kuhlman, in collaboration with chemist Klaus Hahn, is now using Rosetta at UNC-Chapel Hill to build a cellular signaling protein that can be switched on using light. “What’s really cool about this particular switch is that it actually causes the cell to grow in a certain direction,” says Kuhlman. “If you shine a laser on the left-hand side of the cell, the cell will grow towards the left.” Such ”switchable” proteins offer incredibly precise control over when and where a particular protein is active in a cell or patch of cells, providing scientists with a potential means for experimentally disrupting cellular processes in real-time and even manipulating them for therapeutic purposes — for example, by putting a damper on tumor growth.

The holy grail of enzyme engineering is the capability to design an enzyme that catalyzes any reaction imaginable, even those not performed in nature. Two recent articles published by Baker’s team in collaboration with several other leading protein research groups reveal exciting early progress on this front, including the successful design of a novel enzyme that catalyzes the Kemp elimination, a chemical reaction involving the deprotonation of a carbon atom. This may not sound sexy, but it represents a landmark achievement: the engineering of an entirely new protein that performs a chemical reaction no known enzyme can do at 100,000 times the rate the reaction would occur on its own. Based on this proof of concept, it may soon be possible to build enzymes that can recognize and destroy environmental pollutants, transform plant matter into energy, synthesize revolutionary biomaterials — just about anything to which an ambitious chemist might aspire. “There are a huge number of proteins in nature that do all kinds of marvelous things,” says Baker. “But there’s an even larger set of proteins which nature never explored that could do even more marvelous things.”