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2.B.115.  The Membrane Penetration Peptide Transportan-10 (MPP-TP10) Family 

Transportan 10 (TP10) is a 21-residue, cationic, α-helical cell-penetrating peptide that can be used as a delivery vector for various bioactive molecules. Its amino acid sequence is: AGYLLGKINLKALAALAKILL-NH2.  It is believed that TP10 can translocate across neutral lipid membranes passively, possibly as a monomer, without the formation of permanent pore. Bennett et al. 2023 performed molecular dynamics (MD) simulations of TP10W (Y3W variant of TP10) to find the microscopic details of binding, folding and insertion of TP10W to the transmembrane state in POPC bilayers. Binding studies showed that TP10W initially binds to the membrane surface in unstructured configuration, but it spontaneously folds into an α-helical conformation under the lipid head groups. Further insertion of TP10W, changing from a surface bound state to a vertically oriented transmembrane state, was observed. The resulting free energy profile shows a relatively small barrier between these two states, suggesting a possible translocation pathway as a monomer. In fact, unbiased simulation of transmembrane TP10W revealed how a charged Lys side chain can move from one leaflet to the other without a significant free energy cost. Cell penetrating peptides (CPPs) behave differently from pore forming peptides. Their structures and stabilities of the induced transmembrane pores differ (Alimohamadi et al. 2023). Whereas antimicrobial peptides (AMPs) can induce stable transmembrane pores for membranes with a broad range of conditions, pores formed by CPPs are highly labile, consistent with atomistic simulations.

References associated with 2.B.115 family:

Alimohamadi, H., J. de Anda, M.W. Lee, N.W. Schmidt, T. Mandal, and G.C.L. Wong. (2023). How cell penetrating peptides behave differently from pore forming peptides: structure and stability of induced transmembrane pores. bioRxiv. 37546874
Bennett, A.L., K.N. Cranford, A.L. Bates, C.R. Sabatini, and H.S. Lee. (2023). A molecular dynamics study of cell-penetrating peptide transportan-10 (TP10): Binding, folding and insertion to transmembrane state in zwitterionic membrane. Biochim. Biophys. Acta. Biomembr 1866: 184218. [Epub: Ahead of Print] 37634858