Scientists design artificial protein or bring new revolution in medicine and Materials Science

David Baker appreciates the masterpieces of nature "This is my favorite place." The Seattle born scientist stands on a step of the University of Washington and enjoys the snow capped Mount Rainier, 4400 meters above sea level But if you follow him into the lab, you will soon find that the computational biochemist is obviously not satisfied with the gifts of nature, at least in the molecular field On a low coffee table in his office are eight toy sized 3D printed protein replicas Some were circular and spherical, some were tubular and caged, and none of these protein models existed until Baker and his colleagues designed them Over the past few years, thanks to the revolutionary achievements 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 make "life machines" work Now, he and his colleagues have designed and synthesized unnatural proteins in this way, which can play a role in different fields such as medicine and materials At present, the protein designer has developed an experimental HIV vaccine, a new protein designed to resist all influenza virus strains at the same time, a carrier molecule to transport the recombinant DNA into the cells, and a new enzyme to help microorganisms absorb atmospheric carbon dioxide and convert it into useful chemicals The baker team and its collaborators also report that they are making self aggregating "cages" of up to 120 design proteins, which will open the door to a new generation of molecular machines If reading and writing DNA triggered a revolution in molecular biology, the ability to design new proteins would revolutionize almost everything "No one knows what it means," says John moult, a protein folding expert at the University of Maryland, park "It's completely revolutionary." From DNA to protein The mechanism for building proteins is fundamental to all life on earth One way to solve this problem is to determine the structure of the protein through experiments, such as X-ray crystallography and nuclear magnetic resonance (NMR) detection However, these methods are not only slow, but also expensive Even today, the international protein database only stores about 110000 kinds of protein structures, but scientists think there are hundreds of millions or even more kinds of protein Understanding the three-dimensional structure of other proteins helps biochemists to gain insight into the function of each molecule For this reason, Baker and other computer modeling experts try to use computer models to solve the problem of protein folding The researchers came up with two main folding models Among them, homology modeling is to compare the amino acid sequence of a target protein with a template (a protein with similar sequence and known three-dimensional model) But this method has a main problem: although researchers have carried out a lot of expensive X-ray crystallography and nuclear magnetic resonance detection, there are still not enough proteins with known structure can be used as templates When Baker started teaching at Washington University more than 20 years ago, there were fewer templates This prompted him to follow the second approach, which is ab initio modeling, which predicts the structure of proteins by calculating the pull and thrust between adjacent amino acids Baker has also set up a biochemical laboratory to study the interactions between amino acids to help him model With this more powerful computing power, they created a crowdsourcing extension project (Rosetta @ home), which allows people to use idle computers for the computing they need to do, so as to study all potential protein folding Later, they added a video game extension called Foldit, which allows remote users to guide Rosetta's calculations with their unique protein folding perspective This method has attracted more than 1 million users from the international scientific community In addition, it has received more than 20 software packages, ranging from designing new proteins to predicting the interaction between proteins and DNA "One of the smartest things David does is build a community." Neil king, a former postdoctoral fellow at Baker's Institute of protein design at the University of Washington, said About 400 active scientists continue to update and improve Rosetta software The project is free for researchers and non-profit users, but it will charge businesses $35000 Genomics clues Despite Rosetta's success, it has limitations The software is very accurate in predicting the structure of small proteins with amino acid length less than 100, but like other ab initio modeling software, it is difficult to construct large protein molecules A few years ago, Baker began to think of ways to deconstruct most protein structures A technology proposed by computational biologist Chris sander in the 1990s opened a window for him Sanders and others are curious about whether the gene sequence can help to distinguish those amino acid pairs that are far away from each other when they unfold and close to each other after they are folded into three-dimensional structures He reasoned that the neighboring amino acids are very important to the function of protein, and proposed that the specific amino acid pairs which are very necessary to the structure of protein may co evolve Baker and his colleagues realized that scanning the genome can provide new constraints for Rosetta's ab initio modeling They seized the opportunity to write a new software called gremlin, which can compare gene sequences at the same time and present all amino acid pairs that may evolve at the same time "We naturally apply it to Rosetta." Baker said The result is very powerful, it makes Rosetta the best way to model from scratch, and it has more profound meaning Five years ago, ab initio modeling identified only 56 proteins of about 8000 protein families without templates Since then, Baker's team alone has added 900 protein structures Debora marks of Harvard Medical School believes that this approach has been applied to 4700 protein families With the large-scale influx of genomic data into the scientific database, Baker and sander predicted that it would take only two or three years for protein folding models 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 increasingly powerful computing power, Baker's team has mastered the law of protein folding, and they have begun to use this knowledge to try to "transcend the creation of nature" "Almost everything in the biomedical world is affected by being able to make better proteins." Said George church, a synthetic biologist at Harvard University Baker noted that for decades scientists have been pursuing a strategy he calls "Neanderthal protein design," 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 take a shortcut to biological evolution and design proteins to solve modern problems " Moreover, the potential applications of unnatural proteins are not limited to medicine Baker and his colleagues also assembled 120 copies of a molecule called green fluorescent protein into a cage, creating a "nano lantern" that can be studied with light as they move through the tissue The ability to predict how amino acid sequences fold helps to understand how proteins work, thus opening up the design of new protein channels that can catalyze specific chemical reactions or can be used as medicines and materials These protein genes can be synthesized and implanted into microorganisms that produce proteins in nature Last year, Baker's team and collaborators reported that they had designed a new metabolic pathway in bacteria, using an artificially designed protein that allows microbes to turn atmospheric carbon dioxide into fuel and chemicals In what may be the most thought-provoking research so far, the baker team designed proteins that can carry information, and four nucleic acid messengers that mimic DNA bind and wind in the well-known double helix structure of DNA molecules At present, these protein helices can not transmit the genetic information that cells can read But they have far-reaching symbolic significance: protein designers have gone beyond the limits of nature, and now they are limited only by their own imagination "We can use functional proteins to build a whole new world." Baker said.