Release date: 2016-08-04
David Baker appreciates the masterpieces of nature. "This is my favorite place." The scientist, born in Seattle, USA, stood on a step in the University of Washington and said that Rainier Snow Mountain, 4,400 meters above sea level, said. But if you follow him into the lab, you will soon discover that the computational biochemist is obviously not only satisfied with the gifts of nature, at least in the molecular field. In a low coffee table in his office, there are 8 toy-sized 3D printed protein copies.
David Baker is presenting an artificial protein model designed by his team. Image source: Rich Frishman
Some are ring-shaped and globular, some are tubular and cage-shaped, and these protein models did not exist until Baker and colleagues designed them.
Over the past few years, thanks to the revolutionary results of genomics and computer science, Baker's team has solved one of the biggest challenges in modern science: explaining how long chains of amino acids fold into three-dimensional proteins that allow "life machines" to function. Now, he and his colleagues have designed and synthesized non-natural proteins in this way, which can work in different fields from medicine to materials.
Currently, the protein design guru has developed an experimental HIV vaccine, a new protein designed to simultaneously resist all influenza virus strains, a carrier molecule that transports recombinant DNA into cells, and helps microbes absorb atmospheric carbon dioxide. A new enzyme that converts it into a useful chemical. The Baker team and its collaborators also report that they are using self-polymerizing "cage" with up to 120 design proteins, which will open the door to a new generation of molecular machines.
If reading and writing DNA triggers a revolution in molecular biology, the ability to design new proteins will revolutionize almost everything. “No one knows what it means†because it has the potential to influence dozens of different disciplines, says John Moult, a protein folding expert at the University of Maryland, Parker. “It’s completely revolutionary.â€
From DNA to protein
The mechanism by which proteins are constructed is fundamental to all life on Earth. One way to solve this problem is to experimentally determine the structure of the protein, such as by, for example, X-ray crystallization and nuclear magnetic resonance (NMR) detection. However, these methods are not only slow but also expensive. Even today, the International Protein Database stores only about 110,000 protein structures, and scientists believe that there are hundreds of millions of proteins, and more.
Understanding the three-dimensional structure of other proteins helps biochemists gain insight into the function of each molecule. To this end, computer modeling experts such as Baker have attempted to solve the problem of protein folding using computer models.
The researchers thought of two main folding models. Among them, homology modeling is to compare the amino acid sequence of a target protein with a template (a protein having a similar sequence and known for its three-dimensional model). However, this method has a major problem: although researchers have carried out a large number of expensive X-ray crystallization and nuclear magnetic resonance detection, there are still not enough proteins known to be structurally useful as templates.
And more than 20 years ago, when Baker began teaching at the University of Washington, there were fewer templates at the time. This prompted him to follow the second approach, modeling from the beginning, by predicting the structure of the protein by calculating the pull and thrust between adjacent amino acids. Baker also set up a biochemical laboratory to study the interaction between amino acids to help him model.
Through this more powerful computing power, they created a crowd-sourced outreach project (named Rosetta@home) that allows people to use idle computers for the calculations they need to investigate all potential protein folds. . Later, they also added a video game extension called Foldit, which allows remote users to guide Rosetta's calculations with a unique protein folding view. The approach attracted more than 1 million users from the international scientific community, and received more than 20 software packages ranging from designing new proteins to predicting how proteins interact with DNA.
"One of the smartest things David did was to set up a community," said Baker, a former postdoc, researcher at the University of Washington's Protein Design Institute, Neil King. About 400 active scientists continue to update and improve the Rosetta software. The program is free for researchers and non-profit users, but will charge companies $35,000.
Genomics clue
Although Rosetta is very successful, it still has limitations. The software is very accurate in predicting small protein structures with amino acid lengths less than 100, but like other de novo modeling software, it has difficulties in building large protein molecules. A few years ago, Baker began thinking about ways to deconstruct most protein structures.
A technique proposed by computational biologist Chris Sander in the 1990s opened a window for him. Sanders et al. are curious whether gene sequences are useful for distinguishing between pairs of amino acids that are distant from each other when they are unfolded and folded into a three-dimensional structure. He reasoned that the adjacent amino acids were critical to the function of the protein and suggested that specific pairs of amino acids that are essential for protein structure might co-evolve.
Baker and colleagues realized that the scanning genome could provide Rosetta's de novo modeling with new constraints. They seized the opportunity to write a new software called Gremlin that simultaneously compares gene sequences and presents all amino acids that may evolve simultaneously. Correct. “We naturally apply it to Rosetta,†Baker said.
The results are very powerful, it makes Rosetta the best way to model the de novo, and it has far-reaching implications. Five years ago, de novo modeling identified only about 560 proteins of the protein family without templates. Since then, only Baker's team has added 900 protein structures. According to Debora Marks of Harvard Medical School, this approach has been applied to 4,700 protein families. With the massive influx of genomic data into the scientific library, Baker and Sander predict that it would take only two or three years for the protein folding model to have enough co-evolved amino acid pair data to unravel almost any protein structure.
"universal" protein
For Baker, this is just the beginning. With the steady improvement of Rosetta's computing power and the increasing computing power, Baker's team has mastered the law of protein folding, and they have begun to use this knowledge to try to "beyond nature's creations." "Everything in the biomedical world is affected by the ability to make better proteins," said Harvard University's synthetic biologist George Church.
Baker notes that scientists have been pursuing a strategy he calls "Neanderthal Protein Design" for decades, which means that existing protein genes can be distorted to do something new. "We used to be limited by the material that exists in nature... Now we can let the evolution of biology take shortcuts and design proteins that solve modern problems."
Moreover, the potential applications of non-natural proteins are not limited to the medical field. Baker and colleagues also aggregated 120 copies of a molecule called green fluorescent protein into a cage, creating a "nano lantern" that can be aided by light when they move within the tissue.
The ability to predict how amino acid sequences fold helps to understand how proteins work, thereby opening up new protein channels that can catalyze specific chemical reactions or be used as medicines and materials. These protein genes can be implanted into microorganisms that naturally produce proteins after synthesis. Last year, Baker's team and collaborators reported that they designed a new metabolic pathway in bacteria that was created using a manually engineered protein that allows microbes to convert atmospheric carbon dioxide into fuels and chemicals.
In a study that may be called the most thought-provoking study to date, the Baker team designed a protein-carrying protein that mimics the four nucleic acid messengers of DNA that bind and entangle in the well-known double-helix structure of DNA molecules. Now, these protein helix structures are not yet able to transmit genetic information that cells can read. But they have far-reaching symbolism: protein designers have transcended the limits of nature, and now they only have their own imagination. "We can build a whole new world with functional proteins," Baker said.
Source: Chinese Journal of Science
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