Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

16.11.2011
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.

The paper reporting this achievement appears in the Nov. 16 issue of the Journal of American Chemical Society and is available online. Members of Meiler’s team are research assistant Carie Fortenberry, undergraduate students Elizabeth Bowman, Will Proffitt, and Brent Dorr and research assistant professors of biochemistry Joel Harp and Laura Mizoue. The research was supported by grants from the Defense Advanced Research Projects Agency’s protein design project and the National Science Foundation.

David F. Salisbury | Vanderbilt University
Further information:
http://www.vanderbilt.edu

More articles from Life Sciences:

nachricht Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex

nachricht New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Graphene assembled film shows higher thermal conductivity than graphite film

22.06.2018 | Materials Sciences

Fast rising bedrock below West Antarctica reveals an extremely fluid Earth mantle

22.06.2018 | Earth Sciences

Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View

22.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>