In a significant stride forward in the field of analytical biology, researchers from the VIB-VUB Center for Structural Biology in Belgium and the University of Washington School of Medicine in the USA have developed a method to design transmembrane β-barrel (TMB) pores from scratch. These custom-shaped pores enhance the capabilities of single-molecule DNA and RNA sequencing, enabling the use of these technologies in portable, USB-sized devices ideal for point-of-care applications. The details of their findings were recently published in Science.
Designing Nanopores with Precision
Traditionally, nanopore sensors have been limited to naturally occurring proteins, which were not originally intended for sensor functions. Addressing this limitation, the collaborative international team has pioneered a method to engineer protein nanopores with controlled shapes and chemical properties at a molecular level. Using computational design strategies, they have successfully created nanopore channels that offer tunable sizes and conductance, which are more stable and produce less background noise than natural nanopore counterparts.
Dr. Anastassia Vorobieva, group leader at the VIB-VUB Center for Structural Biology, expressed enthusiasm about their progress. "These developments are very exciting. When we started with this idea a few years ago, many people thought it was impossible, because the design and folding of β-sheets is incredibly complex, let alone in lipid membranes. Now we have shown that we can successfully design nanopores with a high success rate, which have stable and reproducible conductance," she remarked.
Practical Applications of Designed Nanopores
The new nanopores are not just theoretical feats; they have practical applications in detecting small molecules such as metabolites, which are essential for metabolomic and diagnostic analyses that traditionally require bulky laboratory equipment. Researchers led by Professor
David Baker from UW Medicine, an HHMI investigator, have extended these designs to develop
proteins that specifically bind to small-molecule metabolites. By splitting the proteins and integrating them into the TMB pores, they have crafted devices capable of detecting single-molecule binding events.
Baker highlighted the significance of their efforts, saying, "This collaboration is a great example of what's possible with protein design. Rather than repurposing biomolecules from nature, we can now create the functions we want from first principles."
The ability to design and use such precise tools suggests that nanopore technology could soon complement or even replace traditional methods like mass spectrometry for certain applications, due to its portability and accessibility.
Looking Forward
Although practical deployment of these technologies in everyday healthcare and research settings is still on the horizon, the implications are promising. The researchers anticipate that in the future, portable devices equipped with a variety of tailor-made nanopores could analyze a broad spectrum of biological molecules, from metabolites and proteins to conducting comprehensive biomolecular sequencing. This advancement stands to democratize and decentralize high-precision molecular analysis, making it accessible outside of specialized laboratories.
Publication Details
Samuel Berhanu et al. Sculpting conducting nanopore size and shape through de novo protein design. Science 385, 282-288 (2024). DOI:10.1126/science.adn3796
Designing Nanopores with Precision
Traditionally, nanopore sensors have been limited to naturally occurring proteins, which were not originally intended for sensor functions. Addressing this limitation, the collaborative international team has pioneered a method to engineer protein nanopores with controlled shapes and chemical properties at a molecular level. Using computational design strategies, they have successfully created nanopore channels that offer tunable sizes and conductance, which are more stable and produce less background noise than natural nanopore counterparts.
Dr. Anastassia Vorobieva, group leader at the VIB-VUB Center for Structural Biology, expressed enthusiasm about their progress. "These developments are very exciting. When we started with this idea a few years ago, many people thought it was impossible, because the design and folding of β-sheets is incredibly complex, let alone in lipid membranes. Now we have shown that we can successfully design nanopores with a high success rate, which have stable and reproducible conductance," she remarked.
Practical Applications of Designed Nanopores
The new nanopores are not just theoretical feats; they have practical applications in detecting small molecules such as metabolites, which are essential for metabolomic and diagnostic analyses that traditionally require bulky laboratory equipment. Researchers led by Professor
David Baker from UW Medicine, an HHMI investigator, have extended these designs to develop
proteins that specifically bind to small-molecule metabolites. By splitting the proteins and integrating them into the TMB pores, they have crafted devices capable of detecting single-molecule binding events.
Baker highlighted the significance of their efforts, saying, "This collaboration is a great example of what's possible with protein design. Rather than repurposing biomolecules from nature, we can now create the functions we want from first principles."
The ability to design and use such precise tools suggests that nanopore technology could soon complement or even replace traditional methods like mass spectrometry for certain applications, due to its portability and accessibility.
Looking Forward
Although practical deployment of these technologies in everyday healthcare and research settings is still on the horizon, the implications are promising. The researchers anticipate that in the future, portable devices equipped with a variety of tailor-made nanopores could analyze a broad spectrum of biological molecules, from metabolites and proteins to conducting comprehensive biomolecular sequencing. This advancement stands to democratize and decentralize high-precision molecular analysis, making it accessible outside of specialized laboratories.
Publication Details
Samuel Berhanu et al. Sculpting conducting nanopore size and shape through de novo protein design. Science 385, 282-288 (2024). DOI:10.1126/science.adn3796