Computational Insights into Membrane Disruption by Cell-Penetrating Peptides
Catalina-Hernández, Èric (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Aguilella-Arzo, Marcel (Universitat Jaume I)
Peralvarez-Marin, Alex (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
López-Martín, Mario (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2025
Resum:	Cell-penetrating peptides (CPPs) can translocate into cells without inducing cytotoxicity. The internalization process implies several steps at different time scales ranging from microseconds to minutes. We combine adaptive Steered Molecular Dynamics (aSMD) with conventional Molecular Dynamics (cMD) to observe nonequilibrium and equilibrium states to study the early mechanisms of peptide-bilayer interaction leading to CPPs internalization. We define three membrane compositions representing bilayer sections, neutral lipids (i. e. , upper leaflet), neutral lipids with cholesterol (i. e. , hydrophobic core), and neutral/negatively charged lipids with cholesterol (i. e. , lower leaflet) to study the energy barriers and disruption mechanisms of Arg9, MAP, and TP2, representing cationic, amphiphilic, and hydrophobic CPPs, respectively. Cholesterol and negatively charged lipids increase the energetic barriers for the peptide-bilayer crossing. TP2 interacts with the bilayer by hydrophobic insertion, while Arg9 disrupts the bilayer by forming transient or stable pores. MAP has shown both behaviors. Collectively, these findings underscore the significance of innovative computational approaches in studying membrane-disruptive peptides and, more specifically, in harnessing their potential for cell penetration.
Ajuts:	Agencia Estatal de Investigación PID2020-120222GB-I00 Agencia Estatal de Investigación PID2022-142795
Nota:	Altres ajuts: acords transformatius de la UAB
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Journal of chemical information and modeling, Vol. 65 (01 2025) , p. 1549-1559, ISSN 1549-960X

DOI: 10.1021/acs.jcim.4c01940
PMID: 39823544

11 p, 5.2 MB

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