Helico-Selective Membrane Transport

forthcoming

Membrane transport regulation is a sophisticated process only achieved by complex pore-forming membrane proteins. Controlling the transportation of bioactive molecules with high selectivity can pioneer a paradigm shift in the precision of membrane-related applications (e.g., drug and gene delivery, biosensing, signaling, metabolic activity manipulation, etc.). Despite the research effort in membrane transport and significant advances in membrane pore engineering, a critical knowledge gap still hinders the development of pore technologies for high-selective membrane translocation processes. Inspired by the recognition mechanisms of transport-specialized membrane proteins, ChiroPore aims to fill this gap by using helical topologies as recognition patterns in nanopore-mediated membrane translocation for the first time. Inspired by natural tagging recognition systems like nuclear nanopores, ChiroPore’s strategy consists of a two-component system in which matching helical topologies are used as recognition motifs, akin to bolt and nut complementarity. A variety of nuts (transmembrane peptide barrels) and bolts (helical peptides) designed with helical complementarities form the basis of a versatile multivalent key-lock system for tag-selective membrane trespassing of bioactive cargo. I will synergistically combine the advantages of existing membrane nanopore engineering strategies into a novel peptide assembly technology to construct membrane pores with precise internal topology. I propose introducing a helical peptide nucleic acid (α-PNA) origami to synthesize membrane-spanning barrels capable of displaying an array of helical topologies. Overall, ChiroPore technology proposes a tag-selective supramolecular membrane transport system that utilizes macromolecular chirality as a recognition motif. This system will contribute to progress toward high-precision delivery, sensing, and communication applications at the cellular level.