A Breakthrough in Protein Design: Codon Index #42
A computational method to design and create proteins that bind to a specific target could give rise to new drugs.
Hello. A computational method to design and create proteins that bind to a specific target could give rise to new drugs. Engineered bacteria, injected into mice, target and destroy tumors using pulses of ultrasound. An improved prime editing protein swaps nucleotides in plants with high efficiency. And a CRISPR tool could help unearth hidden metabolites in the bacterial world teeming beneath our feet.
Protein Design, Backwards
The human genome encodes about 20,000 proteins, each of which is a three-dimensional jigsaw puzzle with pockets, folds, crevices, cracks. The ability to look at a protein's three-dimensional structure, and then reverse engineer a new protein that can bind to that target and block its function — called a binder — would be truly transformative for creating new drugs. A study, published last week in Nature, offers a computational method to do precisely that.
With some high-end computers and clever thinking, researchers in David Baker's lab at the Institute for Protein Design in Seattle have created binder proteins that strongly interact with 12 different protein targets.
Each binder was designed on a computer and then tested in bench experiments. The binders are all smaller than 65 amino acids in length, super stable (they hold their shape) and they bind their target with nanomolar or picomolar affinity. Most drugs used today bind in the nanomolar range; picomolar affinity indicates an even stronger interaction.
Designing binders on a computer, the researchers say, is much like taking on a difficult climbing wall that only has "a few good footholds or handholds distant from each other." Prior computational approaches to design binders focused "on routes involving these footholds/handholds, but this greatly limits the possibilities and there may be no way to connect them into a successful route."
To climb this hypothetical wall, then, the researchers first designed a huge amount of tiny proteins that each, individually, weakly interact with a small part of the target protein's surface. These little proteins are disconnected from one another, like points floating in space, and about one billion of them were designed for each target protein.
This step of the process is all about identification; pick out all the possible handholds and footholds up the climbing wall, no matter how poor they appear.
In the second step, protein backbones were designed to weave around each little protein, tying them together in three-dimensional space. The result is like a string of Christmas lights: each light weakly interacts with the target protein, and a cord holds them all together. The more lights that are roped together, the stronger they grab onto the target protein. In the paper, more than 84,000 protein scaffolds were tested, but only about 34,500 held their shape.
This step is all about testing; have thousands of climbers weave their way up the climbing wall, in unique ways, to find all the possible routes.
In the final step, the number of possible binders were narrowed down. If a similar design appeared on the computer many times, for example, it was assigned a higher score and prioritized it in later steps.
This step is all about validation; if multiple climbers make their way to the top of the wall using a similar route, then that route might be optimal.
These steps, together, offer a general solution for designing very strong binding proteins. Only a small fraction of the many thousands of generated binders actually bind to their protein target, though, so there is room for improvement. Still, the use of this technique for drug discovery — already the subject of a filed patent — seems imminent.
Read more at Nature.
(* = open access, † = review article)
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Computation & Models
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CRISPR & Genetic Engineering
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Medicine & Diagnostics
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Protein & Molecular Engineering
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Tools & Technology
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Until next time,