While Onuchic and Wolynes have been advancing their theories for decades, only recently has it become possible to test their implications for evolution using two very different approaches they developed on the shoulders of their previous work.
One of the algorithms they employ at Rice's Center for Theoretical Biological Physics (CTBP) is called the Associative Memory, Water-Mediated, Structure and Energy Model (AWSEM). Researchers use AWSEM to reverse-engineer the folding of proteins whose structures have been captured by the century-old (but highly time-consuming) process of X-ray crystallography.
The other model, direct coupling analysis (DCA), takes the opposite path. It begins with the genetic roots of a sequence to build a map of how the resulting protein folds. Only with recent advances in gene sequencing has a sufficiently large and growing library of such information become available to test evolution quantitatively.
"Now we have enough data from both sides," Wolynes said. "We can finally confirm that the folding physics we see in our structure models matches the funnels from the evolutionary models."
The researchers chose eight protein families for which they had both genomic information (more than 4,500 sequences each) and at least one structural example to implement their two-track analysis. They used DCA to create a single statistical model for each family of genomic sequences.
The key is the selection temperature, which Onuchic explained is an abstract metric drawn from a protein's actual folding (high) and glass transition (low) temperatures. "When proteins fold, they are searching a physical space, but when proteins evolve they move through a sequence space, where the search consists of changing the sequence of amino acids," he said.<
|Contact: David Ruth|