Do you want to build a protein?

Posted: 11 02, 2015

Written by Amy Rydeen

Doctoral Candidate in Chemistry at UNC

 Screen Shot 2015-10-06 at 12.58.12 PMProtein engineers do.

Most people are familiar with chemical, civil and aerospace engineering. However, not many are aware of ‘designer protein’ engineering. Proteins are responsible for nearly all aspects of life, including cell communication, metabolism, structure and maintenance. Proteins are also commonly utilized by the detergent, food and beverage industries. In particular, proteins that catalyze chemical reactions or enzymes are highly valuable. Enzymes are the most efficient catalysts ever known, increasing the speed of a chemical reaction up to 1021 fold! Protein engineers create new enzymes with abilities and functions designed by the engineer.

How does one build a protein?

Screen Shot 2015-10-06 at 2.57.58 PMOption 1: Start from scratch.

Proteins are made of building blocks called amino acids. Similar to how letters are strung together to form words with specific meanings, amino acids are assembled to create proteins with a certain fold and function.

Dr. David Baker’s lab at the University of Washington specializes in creating proteins with new properties from scratch. In 2003, the engineers created a protein with a structure never before found in nature using a computational program called Rosetta. Rosetta was used to predict a sequence of amino acids with the potential to adopt the researchers desired structure. Sure enough, assembling the proper amino acids resulted in a novel protein fold1.

Option 2: Modify Mother Nature’s work.

For engineers not keen on heavy computational work, an alternative route to create proteins with new function is to modify an existing protein. In nature, new chemical reactivity can arise from the accumulation of mutations, or changes in the amino acid composition of a protein. Protein engineers mimic evolution in the lab by deliberately mutating the amino acids of an enzyme. Enzymes are commonly mutated and characterized for improved stability, activity or the appearance of new reactivity. Mutations are also commonly made to expand the set of molecules an enzyme can recognize.

Option 3: Integrate non-natural building blocks.Protein Engineering

Protein engineers can build enzymes containing non-natural building blocks, amino acids, utilizing genetic code expansion technology. In biology, proteins are made of combinations of the 20 naturally occurring amino acids, encoded by 64 codons. Genetic code expansion assigns a rare codon to a designer amino acid created by the researcher. Non-natural designer amino acids have been used to create proteins with novel abilities2.

Why build designer proteins?

Proteins are biological macromolecules. Consequently, they operate in water and in air, very mild conditions. A goal of the chemical industry is to reduce environmentally harmful waste. Therefore, enzymes are an attractive alternative or complement to traditional organic chemistry methods. Replacing organic reagents with enzymes reduces the amount of harmful solvents and waste generated. A major success in the field was the engineering of an enzyme that replaced a synthetic catalyst in the production of the antidiabetic compound, sitagliptin3.   The enzymatic process eliminated harmful waste and reduced costs.

Protein engineering has tackled many challenges thus far but there remain many exciting opportunities. For example, many reactions employed by chemical industries do not exist in nature. Therefore, creating enzymes with non-natural chemical reactivity is a contemporary goal.


1.) Science (2003) 302, 1364

2.) Nature Reviews Molecular Cell Biology (2012) 13, 168

3.) Science(2010) 329, 305

Peer edited by Neerali Patel

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This article was co-published on the SWAC Blog, The Pipettepen.

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