Mimicking nature’s biological membrane channels
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The front cover of ACS Nano shows the barrel-like architecture of the de novo-designed membrane channel (orange) in between a lipid bilayer (blue) as a sugar molecule (red) tries to pass through the channel. Cover art by Yuhao Li and Alex Noy (both LLNL).
Researchers from Lawrence Livermore National Laboratory (LLNL), the University of Washington (UW) and Pacific Northwest National Laboratory (PNNL) have successfully designed and tested de novo (from the beginning) synthetic protein channels that mimic the natural precision of biological membrane pores.
Their research, appearing on the front cover of the January 2025 issue of ACS Nano, aims to harness the power of modern protein design to create synthetic channels that could match or even surpass the capabilities of natural ones.
Biological membrane channels, such as those found in living cells, are nature's gatekeepers. They allow water, ions and small molecules to pass through with remarkable efficiency and selectivity. However, replicating this functionality in synthetic systems has been a major challenge. While previous attempts using artificial materials like nanotubes and DNA structures have shown a lot of promise, they still lack the refined performance and versatility of biological membrane pores.
David Baker of UW, who recently received the 2024 Nobel Prize for his work on de novo protein design, led the UW part of the team in building transmembrane β-barrel (TMB) pores from scratch using advanced computational tools to control their size and structure at the atomic level. Commonly found in the outer membranes of bacteria, mitochondria and chloroplasts, TMB pores play a crucial role in transporting molecules across the membrane. TMB pores have been targeted by scientists for applications in disease detection, drug delivery, and environmental monitoring.
Three versions of these protein pores were created—TMB8, TMB10 and TMB12—each with increasing pore sizes. By carefully designing the number of strands in the β-barrel structure, the team could control the size of the inner channel, ranging from 0.5 to 1.5 nanometers. These synthetic proteins were then integrated into lipid membranes (see cover image) to test their ability to transport water, ions and solutes.
LLNL and PNNL teams, which included Yuhao Li, Zhongwu Li, Jobaer Abdullah, Sydney Myers and Alex Noy of LLNL’s Physical and Life Sciences organization, then combined experimental measurements and molecular dynamics simulations to explore transport properties of these proteins, finding that their synthetic protein channels performed remarkably well, with water and ion transport and solute size exclusion (allowing some molecules to pass through but blocking others) properties closely resembling those of natural membrane pores.
Looking ahead, the team is excited about the endless possibilities these de novo-designed protein channels bring to a variety of applications.
–Physical and Life Sciences Communications Team
