Tech Review has an article highlighting work by David Baker and colleagues. Baker and co-workers have de novo designed a handful of non-natural enzymes that successfully catalyze a specific chemical reaction, one with no naturally known enzyme. The work, published in Science, uses a pretty elegant procedure. I will update this post after I get a chance to grab the paper tomorrow.
1. First a putative active site was designed using geometric and chemical restrictions
2. Following active site design, a set of proteins containing such functionality were designed (the Baker groups call to fame). The proteins were scored and ranked on their ability to accommodate the reactants
The group followed up by synthesizing 72 of the designed enzymes and found that 32 of the proteins were able to catalyze the reaction with the best getting a 10^4x speedup. While that number is significantly lower than naturally occurring enzymes, just the fact that the Baker group was able to do so and with a pretty decent success rate (very decent in my book) is saying something. Like Baker, I think a combination of directed evolution and in silico prediction might help design more effective proteins. In addition, at least for this particular example, for the computational methods to be really successful, there has to be some accounting for electronic structure.
It’s good to see the field take some steps after being relatively stagnant in recent years. We need to look at problems in two ways, de novo, and by modifying/enhancing existing proteins.
I completely agree. It's something that people don't understand, including some in the life sciences.
Current in silico methods use too many approximations. It's amazing that they do as well as they do. I don't think you can wait for in silico methods at all, but they can be used for candidate selection or to try and understand mechanisms and of course, in 30 years or so when our computers are fast enough then perhaps everything will be designed computationally.
In slico! vs directed evolution. I am always amazed at how much better directed evolution methods are vs in silico. I really think we should spend more time in developing screening methodology and platforms that allow directed evolution screens to be performed in a more reliable manner. Otherwise much of the promise of synthetic biology may fade before we wait for the in-silico methods to catch up. Although I am sure these results are a significant improvement , it is humbling to see how much the gap between these two methods are for engineering function
Strides in protein design
Tech Review has an article highlighting work by David Baker and colleagues. Baker and co-workers have de novo designed a handful of non-natural enzymes that successfully catalyze a specific chemical reaction, one with no naturally known enzyme. The work, published in Science, uses a pretty elegant procedure. I will update this post after I get a chance to grab the paper tomorrow.
1. First a putative active site was designed using geometric and chemical restrictions
2. Following active site design, a set of proteins containing such functionality were designed (the Baker groups call to fame). The proteins were scored and ranked on their ability to accommodate the reactants
The group followed up by synthesizing 72 of the designed enzymes and found that 32 of the proteins were able to catalyze the reaction with the best getting a 10^4x speedup. While that number is significantly lower than naturally occurring enzymes, just the fact that the Baker group was able to do so and with a pretty decent success rate (very decent in my book) is saying something. Like Baker, I think a combination of directed evolution and in silico prediction might help design more effective proteins. In addition, at least for this particular example, for the computational methods to be really successful, there has to be some accounting for electronic structure.
It’s good to see the field take some steps after being relatively stagnant in recent years. We need to look at problems in two ways, de novo, and by modifying/enhancing existing proteins.
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