Friday, April 19, 2013

Proteins by design – expanding on nature

Yesterday at the CAPRI meeting,  a heartfelt plea from Dr Ilya Vakser of the University of Kansas really caught my ear. “There’s so much data and so few people to dig into it!” he cried.

Dr David Baker of Washington University, Seattle introduced the CAPRI meeting to the design of proteins, and how they interact with each other. It could all have been different though – first Baker polled the audience to see whether they would prefer to hear about structural modelling with sparse data instead.  That’s the first time I’ve ever seen audience participation in a talk at that level – it was practically the conference equivalent of X Factor.

Once he had the correct set of slides cued up, Baker started out by praising the excellent job that Mother Nature’s naturally occurring proteins do. They solve the challenges that biological evolution presents perfectly, such as capturing and storing energy, making and breaking down molecules. However, thanks to modern life we now find ourselves faced with challenges that are not thrown at us by nature alone, such as global warming and living longer. The question for protein designers is can they design a whole new world of synthetic proteins to address these challenges? “Ideally we should take less than 2 billion years to figure out how to do it,” said Baker.

There are a number of areas to focus on, including designing the next generation of therapeutic proteins, building scaffolds for enzyme reactions, and self assembling cages to carry drugs and vaccines into the body. The process starts by calculating a sequence of biological building blocks known as amino acids that might give the desired protein structure and function. You read off the sequence, and translate that back into a DNA sequence that would encode the synthetic protein. Once you have a DNA sequence, you can then make the gene that will then build the protein you want. As a non-biologist, this was the part that I found like an extract from a sci-fi novel – you can now buy a custom gene over the internet, and then back comes the DNA encoder that you need. Build your protein, then see if it does what you want.

But the process starts with finding the sequence with the lowest energy configuration – because molecules like to exist at the lowest possible energy. It’s difficult to know whether the structure you have found is the lowest possible however and this is where non-scientists can get involved. Rosetta@home is a volunteer computing project which uses spare computer time donated by volunteers to look for the lowest energy versions of protein sequences and send back the solutions. Luckily the synthetic protein structures are somewhat easier to predict than naturally evolved proteins.

Baker ran through some more key challenges for protein builders, such as designing binding between proteins when looking for ways to treat Spanish flu, and finding methods to inhibit intracellular interactions when you need to target just one black sheep out of a whole family of proteins, for example the Epstein-Barr virus. 

FoldIt puzzle screenshot
One question Baker asked is, "Why are the enzymes we design ourselves so lousy?" Here he turned to the FoldIt volunteer community. FoldIt was dreamed up in response to Rossetta@home users who wanted a bit more of a challenge. FoldIt poses protein folding puzzles to users, to check protein design sequences and see if in silico folding predications are accurate.

One example is the de novo designed Diels-Alderase, an enzyme for forming carbon-carbon bonds.  "Can we improve activity by remodelling active site loops?" asked Baker. "Let’s ask the Foldit community!" He gave them a solve it game for FoldIt players and one successful player increased the interaction 20 fold. When the crystal structure was solved, it was found to be very similar to the prediction. ”Now I’ve come to be a big believer in the concept that if you don’t know the answer, ask more people until you do!” said Baker. A response to Vaksar’s plea earlier perhaps – the people to analyse your data are out there, you just need to give them the tools to do it.

(For more information about volunteer computing, read the e-ScienceBriefing at

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