Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Design and Build First Artificial Protein

21.11.2003


Using sophisticated computer algorithms running on standard desktop computers, researchers have designed and constructed a novel functional protein that is not found in nature. The achievement should enable researchers to explore larger questions about how proteins evolved and why nature “chose” certain protein folds over others.


A computer-generated image of the artificial protein, Top7
Image: Gautam Dantas/University of Washington



The ability to specify and design artificial proteins also opens the way for researchers to engineer artificial protein enzymes for use as medicines or industrial catalysts, said the study’s lead author, Howard Hughes Medical Institute investigator David Baker at the University of Washington.

Baker and colleagues Brian Kuhlman, who is now at the University of North Carolina, Chapel Hill, and graduate student Gautam Dantas at the University of Washington, published their studies in the November 21, 2003, issue of the journal Science. The scientists collaborated on the studies with other researchers at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle.


Proteins are initially synthesized as long chains of amino acids and they cannot function properly until they fold into intricate globular structures. Understanding and predicting the rules that govern this complex folding process — involving the folding of the main backbone and the packing of the molecular side chains of the amino acids — is one of the central problems of biology.

According to Baker, the ability to specify a desired folded protein structure and then to create that protein offers powerful scientific and practical benefits. “First, specifying a protein fold and then designing that protein is a very stringent test of our current understanding of the forces and energetics of macromolecular systems,” he said. “Because designing something that’s completely new means you can’t copy any aspect from nature.

“Secondly, if one can design completely new structures, one can potentially design novel molecular machines — proteins for carrying out new functions as therapeutics, catalysts, etc. And finally, there’s the evolutionary question of whether the folds that are sampled in nature are the limit of what’s possible; or whether there are quite different folds that are also possible,” he said. “Basically, we want to understand whether nature only sampled a subset of what’s possible,” said Baker.

The challenges of designing an amino acid sequence to fold into a new structure were considerable, said Baker. “If you draw on the back of an envelope some arbitrary protein structure, it might be that there is simply no amino acid sequence that will fold up to that structure. We had to develop methods to computationally sample possible structures similar to the one drawn on the back of the envelope, searching for a conformation for which there exists a very low energy amino acid sequence,” he said.

Baker and his colleagues took advantage of methods for sampling alternative protein structures that they have been developing for some time as part of the Rosetta ab initio protein structure prediction methodology. “Indeed, the integration of protein design algorithms (to identify low energy amino acid sequences for a fixed protein structure) with protein structure-prediction algorithms (which identify low energy protein structures for a fixed amino acid sequence) was a key ingredient of our success,” Baker said. He likened the problem to the three-dimensional version of attempting to create a specified outline for a jigsaw puzzle, given only a certain number of pieces — the equivalent of the 20 known amino acids in nature. In addition, he said, these amino acids can rotate into a number of different conformations.

“At each position, you can have one of the twenty amino acids, and for each of those amino acids you can have on the order of ten different shapes,” he said. “So, you have two hundred different possible shapes for each piece. With those restrictions, it may be that there are some outlines to this jigsaw puzzle that you just cannot achieve. So you need to have a way of changing the boundary to find a protein that can actually be made, because the main constraint is that the side chains fit together perfectly in the interior of the protein.

“Thus, the problem is that the number of alternatives can be huge. Even for one fixed backbone conformation, you have an astronomical number of possible amino acid sequences,” said Baker. “So, we needed a computational approach to search the huge space of possible conformations and possible amino acid sequences efficiently.”

In their design and construction effort, the scientists chose a version of a globular protein of a type called an alpha/beta conformation that was not found in nature. “We chose this conformation because there are many of this type that are currently found in nature, but there are glaring examples of possible folds that haven’t been seen yet,” he said. “We chose a fold that has not been observed in nature.”

Their computational design approach was iterative, in that they specified a starting backbone conformation and identified the lowest energy amino acid sequence for this conformation using the RosettaDesign program they had developed previously RosettaDesign is available free to academic groups at www.unc.edu/kuhlmanpg/rosettadesign.htm.

They then kept the amino acid sequence fixed and used the Rosetta structure prediction methodology they had previously used successfully for ab initio protein structure prediction to identify the lowest energy backbone conformation for this sequence. Finally, they fed the results back into the design process to generate a new sequence predicted to fold to the new backbone conformation. After repeating the sequence optimization and structure prediction steps 10 times, they arrived at a protein sequence and structure predicted to have lower energy than naturally occurring proteins in the same size range.

The result was a 93-amino acid protein structure they called Top7. “It’s called Top7, because there was a previous generation of proteins that seemed to fold right and were stable, but they didn’t appear to have the perfect packing seen in native proteins,” said Baker.

The researchers synthesized Top7 to determine its real-life, three-dimensional structure using x-ray crystallography. As the x-rays pass through and bounce off of atoms in the crystal, they leave a diffraction pattern, which can then be analyzed to determine the three-dimensional shape of the protein.

“One of the real surprises came when we actually solved the crystal structure and found it to be marvelously close to what we had been trying to make,” said Baker. “That gave us encouragement that we were on the right track.”

According to Baker, the achievement of designing a specified protein fold has important implications for the future of protein design. “Probably the most important lesson is that we can now design completely new proteins that are very stable and are very close in structure to what we were aiming for,” he said. “And secondly, this design shows that our understanding and description of the energetics of proteins and other macromolecules cannot be too far off; otherwise, we never would have been able to design a completely new molecule with this accuracy.”

The next big challenge, said Baker, is to design and build proteins with specified functions, an effort that is now underway in his laboratory.

Jim Keeley | HHMI
Further information:
http://www.hhmi.org/news/baker3.html

More articles from Information Technology:

nachricht A novel hybrid UAV that may change the way people operate drones
28.03.2017 | Science China Press

nachricht Timing a space laser with a NASA-style stopwatch
28.03.2017 | NASA/Goddard Space Flight Center

All articles from Information Technology >>>

The most recent press releases about innovation >>>

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

Im Focus: A Challenging European Research Project to Develop New Tiny Microscopes

The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.

To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Transport of molecular motors into cilia

28.03.2017 | Life Sciences

A novel hybrid UAV that may change the way people operate drones

28.03.2017 | Information Technology

NASA spacecraft investigate clues in radiation belts

28.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>