20.500.12556/DKUM-97665 pH-Responsive peptide nanopores are stabilized by lipid and water-mediated hydrogen bonding networks 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. nanopores macromolecular cargo biomedical applications nanopore makromolekule biomedicina true false true Royal society of chemistry Angleški jezik Slovenski jezik https://www.rsc.org/publishing/journals/nanoscale Članek v reviji 2026-03-31 07:10:19 2026-03-31 07:10:20 2026-04-01 03:10:51 0000-00-00 00:00:00 2026 0 0 str. 3598–3612 Vol. 18 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 2025-08-03 2026-01-04 2026-01-06 577 272733699 10.1039/D5NR03276H 2040-3372 d5nr03276h.pdf d5nr03276h.pdf 1 9E92827D9D6870283C11B23C377CBB2A 13821d03cf0d2c8c015cc8db40e1117b4d65dc0612dc0eac7c26fb862052bef9 b5bb594a-2cc0-11f1-b3ef-00155d0001a1 https://dk.um.si/Dokument.php?lang=slv&id=204912 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0