School Seminar Program

Bridges, wires, and a chameleon: Crossing the membrane’s fortifications

Professor Sean Smith
Applied Maths, Research School of Physics, ANU

Peptides are a class of biological molecules built from chains of up to 50 amino acids. The mechanism by which cell-penetrating peptides and antimicrobial peptides cross plasma membranes is unknown, as is how cell-penetrating peptides facilitate drug delivery, mediating the transport of small molecules. Once non-disruptive and non-endocytotic pathways are excluded, pore formation is one of the proposed mechanisms, including toroidal, barrel-stave, or carpet models. Spontaneous pores have been observed in coarse-grained simulations and less often in molecular dynamics simulations. While pores are widely assumed and inferred, there is no unambiguous experimental evidence of the existence of pores. Some recent experimental studies contradict the mechanistic picture of pore formation, however, highlighting the possibility of a direct translocation pathway that is both non-disruptive and non-endocytotic.

In this work, we propose a model for peptide (linear and dendritic) translocation which does not require the presence of pores and which potentially accords with such experiments. We suggest that a charged peptide, as it experiences an increasingly hydrophobic environment within the membrane surface, can utilize a proton chain transfer mechanism to shed its protons to counter ions or potentially phospholipid head groups in the membrane skin region, thereby becoming compatible with the hydrophobic interior of the membrane. This increases the likelihood to move into the highly hydrophobic core of the membrane and ultimately reach the opposite leaflet to re-acquire protons again, suggesting a potential “chameleon” mechanism for non-disruptive and non-endocytotic membrane translocation. Our molecular dynamics simulations reveal stability of peptide bridges joining two membrane leaflets and demonstrate that this can facilitate cross-membrane transport of small drug molecules.

Sean Smith commenced as Director of the NCI in January 2018 and is conjointly Professor of computational nanomaterials science and technology at the ANU. He has extensive theoretical and computational research experience in chemistry, nanomaterials and nano-bio science and technology. Sean’s research is directed at an integrated materials design and discovery program, fuelled by a tight coupling of high performance materials simulations within his lab with materials synthesis, characterization and functionality testing with collaborators, nationally and internationally. This leads to new fundamental scientific discoveries as well as new materials and biomaterials applications and technologies, with associated commercialization activities.

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