Navigation Links
Creation of the largest human-designed protein boosts protein engineering efforts

If Guinness World Records had a category for the largest human-designed protein, then a team of Vanderbilt chemists would have just claimed it.

They have designed and successfully synthesized a variant of a protein that nature uses to manufacture the essential amino acid histidine. It is more than twice the size of the previous record holder, a protein created by researchers at the University of Washington in 2003.

The synthetic protein, designated FLR, validates a new approach which the Vanderbilt scientists have developed that allows them to design functional artificial proteins substantially larger than previously possible.

"We now have the algorithms we need to engineer large proteins with shapes that you don't see in nature. This gives us the tools we need to create new, more effective antibodies and other beneficial proteins," said Jens Meiler, the associate professor of chemistry at Vanderbilt who led the effort.

Recently, protein engineers have verified a potential treatment strategy for HIV by using designed protein vaccines in mice and have designed artificial proteins that mimic antibodies in broadly neutralizing flu infections. The technique developed at Vanderbilt promises to expand the scope of these efforts substantially.

That is important because proteins are the most important molecules in living cells. They perform most of the vital tasks that take place within a living organism. There are hundreds of thousands of different proteins. They come in a variety of shapes and sizes. They can be round or long and thin, rigid or flexible. But they are all made out of linear chains of 20 amino acids encoded in the genome of the organism.

Proteins assume this variety of shapes and sizes by the manner in which they bunch and fold. This complex process takes two steps. First, small numbers of adjacent amino acids form what scientists call secondary structures: the most common of which are a rod-like spiral shape called the alpha-helix and a flat, pleated shape called the beta-sheet. These secondary structures, in turn, interact, fold and coil to form the protein's three-dimensional shape, which is the key to its function.

Over the past 10 years an increasing number of proteins that don't exist in nature have been designed "in silico" (in a computer). Scientists use sophisticated protein modeling software that incorporates the relevant laws of physics and chemistry to find amino acid sequences that fold into stable forms and have specific functions.

Imagine making a necklace 10 beads long with beads that come in 20 different colors. There are more than 10 trillion different combinations to choose among. This provides an idea of the complexity involved in designing novel proteins. For a protein of a given size, the modeling software creates millions of versions by putting each amino acid in every position and evaluating the stability of the resulting molecule. This takes a tremendous amount of computing power which skyrockets as the length of the protein increases.

"The current limit of this approach, even using the fastest supercomputers, is about 120 amino acids," said Meiler. The previous record holder contained 106 amino acids. The newly designed protein contains 242 amino acids. The Vanderbilt group got around this limit by modifying the widely used protein engineering platform called ROSETTA so that it can incorporate symmetry in the design process.

Their success provides new support for a controversial theory about protein evolution called the gene duplication and fusion hypothesis. The advantage of small proteins is that they can evolve rapidly in response to changing conditions, but larger proteins can perform more complex functions. Nature found a way to get both advantages by selecting small proteins that can interact with other copies of themselves to form larger proteins, which are called dimers. Once useful dimers have been created the gene that coded for the original protein is duplicated and fused to form a new gene that can directly produce the dimer. After it is created, the dimer gene is gradually modified by natural selection to make it more efficient or develop new functions.

Because they have two identical halves, dimers have a large degree of symmetry. By taking these symmetries into account, the Vanderbilt group was able to substantially reduce the amount of computing time required to create the FLR protein. Using 400 processors of the supercomputer at Vanderbilt's Advanced Computing Center for Research and Education, it took 10 days of continuous processing to find the most stable configuration.

To check the accuracy of their design, the researchers synthesized the DNA sequence that produces the protein, inserted it in E.coli bacteria and determined that they produced the protein and it folded properly.

The FLR protein assumes a 3-D shape called a TIM barrel, which is found in 10 percent of proteins and is particularly prevalent among enzymes. It is formed from eight beta strands that are surrounded by eight alpha helices arranged in a hexagonal shape like a tiny barrel.


Contact: David F. Salisbury
Vanderbilt University

Related biology news :

1. Scientists propose the creation of a new type of seed bank
2. Gladstone scientists identify key factors in heart cell creation
3. U of Minnesota study finds high school teachers influence student views of evolution & creationism
4. Fate Therapeutics announces creation of small molecule platform for commercial-scale reprogramming
5. Exposure to young triggers new neuron creation in females exhibiting maternal behavior
6. $25M NSF center established to investigate the creation of biological machines
7. Creation of the first frozen repository for Hawaiian coral
8. New collaborative process can help improve management of marine recreational fisheries
9. NSF awards $3.75 million grant to New York Plant Genome Consortium for the creation of BigPlant v1.0
10. Study eyes fluoxetine in recreational waters
11. Oregon Farm to School bill would benefit health through job creation, study finds
Post Your Comments:
(Date:9/28/2015)... , Sept. 28, 2015 ... today that its expedited traveler service is ... platform transforms travel, bringing a frictionless experience, ... members. "CLEAR offers our travelers ... customer service," said Jim Smith , ...
(Date:9/28/2015)... 2015 The global image ... 12.03 billion by 2020, growing at a CAGR of ... Backside Illumination (BSI) technique to improve picture quality are ...      (Logo: , The ... reduce loss and, thus, reduce the noise interference and ...
(Date:9/28/2015)... Calif. , Sept. 28, 2015 Synaptics ... human interface solutions, today announced that Lenovo has selected ... fingerprint sensor, FS4202, for its latest smartphone, the Vibe ... password-free access to unlock the device and provide swift ... The feature-rich Natural ID FS4202 sensor solution ...
Breaking Biology News(10 mins):
(Date:10/12/2015)... , Oct. 12, 2015  Patara Pharma, ... allergic and inflammatory diseases and conditions, today announced ... preferred stock financing. Concurrent with the close of ... into a Loan and Security Agreement with Silicon ... to $7 million. Patara will use the funds ...
(Date:10/12/2015)... offers user-friendly, ... online experience --> ... for enriched online experience --> ... to print version for enriched online experience ... and medical information products and services, announced today that ...
(Date:10/12/2015)... ... October 12, 2015 , ... Dr. ... Srinivasan, has joined the firm as a Premier Expert consultant. NDA Partners ... to bring extraordinary value to the company's clients. Premier Experts collaborate to ...
(Date:10/12/2015)... ... October 12, 2015 , ... LifeTrak , a ... of LifeTrak Zoom, the world’s first amphibious fitness tracker that seeks to meet the ... technology and accurate heart rate monitoring both in water and on land, ...
Breaking Biology Technology: