| Title: | pH-Responsive peptide nanopores are stabilized by lipid and water-mediated hydrogen bonding networks |
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| Authors: | ID Bondar, Ana-Nicoleta (Author)
ID Lešnik, Samo (Author)
ID Hristova, Kalina (Author)
ID Wimley, William C. (Author) |
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| Files: |  d5nr03276h.pdf (6,94 MB)
MD5: 9E92827D9D6870283C11B23C377CBB2A
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| Language: | English |
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| Work type: | Article |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: | FKKT - Faculty of Chemistry and Chemical Engineering
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| Abstract: | Membrane-spanning nanopores that allow controlled passage of macromolecular cargo across cell membranes can empower many biomedical applications. Such nanopores are formed, in a pH-responsive manner, by the synthetically evolved “pHD peptide” family. pHD peptides fold into amphipathic α-helices, but have many charged and polar residues and are thus not predicted by classical hydropathy analyses to fold into membrane-spanning structures. Yet, when the pH is below ∼6, pHD peptides readily self-assemble into nanopores, even at low concentration. Knowledge of the molecular structure of the pHD peptide pore is needed for further rational design and optimization of nanopore-forming activity targeted to specific membranes and pH conditions. To this end, we have carried out extensive atomistic molecular dynamics simulations to explore the protonation-dependent structure and dynamics of nanopores created by the peptide pHD108. Simulations and graph-based analyses of hydrogen bonding reveal that, in the nanopore, the numerous carboxylate and carboxyamide sidechains form a dense, water-bridged H-bond network across the bilayer. In this network, direct H-bonds between neighboring peptides are few. Instead, the network is dominated by water-bridged intrapeptide interactions and by water-bridged interactions with the headgroups of many lipid molecules with unusual conformations and orientations. The lipids in the H-bond network make critical contributions to nanopore stabilization. These studies reveal a non-classical means of stabilizing nanopores in bilayers formed by highly charged peptides, creating an avenue towards engineering of membrane-embedded structures. |
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| Keywords: | nanopores, macromolecular cargo, biomedical applications |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Submitted for review: | 03.08.2025 |
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| Article acceptance date: | 04.01.2026 |
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| Publication date: | 06.01.2026 |
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| Publisher: | Royal society of chemistry |
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| Year of publishing: | 2026 |
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| Number of pages: | str. 3598–3612 |
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| Numbering: | Vol. 18 |
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| PID: | 20.500.12556/DKUM-97665  |
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| UDC: | 577 |
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| ISSN on article: | 2040-3372 |
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| COBISS.SI-ID: | 272733699 |
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| DOI: | 10.1039/D5NR03276H |
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| Publication date in DKUM: | 31.03.2026 |
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| Views: | 108 |
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| Downloads: | 5 |
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| Metadata: |    |
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| Categories: | Misc.
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