Software gives fast-track to improved enzymes
predict the activity of enzymes, potentially improving the design
of new drugs and industrial reagents.
The team of Penn State chemists and chemical engineers say the package, called FamClash, can reliably predict the activity of 'hybrid' enzymes, i.e. those made by joining together similar enzymes from two different organisms. This is a common approach when trying to develop enzymes that work in unnatural conditions, such as low or high temperatures and acidic environments.
The researchers report in the online issue of the Proceedings of the National Academy of Sciences that FamClash can identify incompatible structures in the hybrid enzymes and recommends ways in which the molecules can be engineered to bypass them.
"We have worked out ways to make libraries of novel enzymes by splicing proteins together," said Alexander Horswill, postdoctoral fellow in chemistry at Penn State. "We wanted to know how active the new enzymes would be compared to the wild type."
The software is expected to find early applications in industrial processes, which use enzymes when reactions are too slow or too expensive to carry out without a catalytic boost. But there is no barrier to using the software in other applications such as rational drug design.
In the PNAS study, the researchers used enzymes from Escherichia coli and Bacillus subtilis, two common bacteria. Both produce forms of dihydrofolate reductases or DHFR that are 44 per cent identical at the protein level. They first had the computer programme generate all the hybrids that could be formed from then looked at each combination in each hybrid for pair clashes.
The hybrid combinations were then ranked for predicted enzyme activity based on the number of clashes present.
"It is very helpful to experimentalists to know where introduced crossovers will produce high activity," says Horswill. "The long-term goal is to engineer enzymes for specific functions," he added.
