Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Wednesday Speaker Abstracts

MOLECULAR DYNAMICS SIMULATIONS OF PORE-FORMING PHD PEPTIDES Denisa-Sonia Andronic 1 ; Shalmali Kharche 2 ; Hrushikesh Malshikare 2 ; Durba Sengupta 2 ; Kalina Hristova 3,4 ; William C Wimley 5 ; Ana-Nicoleta Bondar 6,7 ; 1 Faculty of Physics, University of Bucharest, Experimental and Computational Biophysics, Medical Physics, Magurele, Romania 2 CSIR-National Chemical Laboratory, Division of Physical and Materials Chemistry, Pune, India 3 Johns Hopkins University, Department of Materials Science and Engineering, Whiting School of Engineering, Baltimore, MD, USA 4 Johns Hopkins University, Institute for NanoBioTechnology, Baltimore, MD, USA 5 Tulane University School of Medicine, Department of Biochemistry and Molecular Biology, New Orleans, LA, USA 6 Faculty of Physics, University of Bucharest, Department of Electricity, Solid Physics and Biophysics, Magurele, Romania 7 Forschungszentrum Jülich, Institute of Computational Biomedicine (IAS-5/INM-9), Jülich, Germany To overcome the cellular membrane barrier, direct intracellular delivery of macromolecular therapeutics, such as proteins, enzymes or antibodies, would require a cargo delivery system and such a system could be constituted by the synthetically evolved pHD peptides; pHD peptides have the ability to assemble into stable membrane nanopores at an acidic pH, a characteristic of the extracellular environment of cancer cells, and at low concentrations, that are non-toxic to healthy cells. Since the three-dimensional structures of these pores are not amenable to traditional structural biology methods, experimental efforts must be combined with computational approaches to decipher the reaction coordinate and the molecular interactions that govern the pore-formation process. Here we use both coarse-grained and atomistic molecular dynamics simulations on model systems of pHD108 8-mers embedded in hydrated lipid bilayers of different thickness. In the coarse-grained representation with standard parametrization, the peptides de-insert rapidly from the bilayer. By contrast, the microsecond-long atomistic simulations show stable pores in all of the lipid bilayers we study, with membrane-embedded peptides and water molecules passing through. The atomistic simulations also reveal that the pore-associated lipids sample highly unusual conformations, with their headgroups deep into the membrane plane and their acyl chains either splayed or parallel to the membrane surface. Taken together, the assembly of these simulations suggest potential methodological developments for more accurate treatment of pore formation at the coarse-grained level, while also offering insights into the peptide-lipid interactions that stabilize the pores. The authors gratefully acknowledge computing time on the supercomputer JURECA at the Forschungszentrum Jülich under grants no. TOXINTOCURE and PHDPORES. This work was funded by the National Institutes of Health NIH R01 GM 151326.

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