Understanding the molecular mechanisms governing nanoparticle-membrane interactions is of prime importance for drug delivery and biomedical applications. Neutron reflectometry (NR) experiments are combined with atomistic and coarse-grained molecular dynamics (MD) simulations to study the interaction between cationic gold nanoparticles (AuNPs) and model lipid membranes composed of a mixture of zwitterionic di-stearoyl-phosphatidylcholine (DSPC) and anionic di-stearoyl-phosphatidylglycerol (DSPG). MD simulations show that the interaction between AuNPs and a pure DSPC lipid bilayer is modulated by a free energy barrier. This can be overcome by increasing temperature, which promotes an irreversible AuNP incorporation into the lipid bilayer. NR experiments confirm the encapsulation of the AuNPs within the lipid bilayer at temperatures around 55 °C. In contrast, the AuNP adsorption is weak and impaired by heating for a DSPC-DSPG (3:1) lipid bilayer. These results demonstrate that both the lipid charge and the temperature play pivotal roles in AuNP-membrane interactions. Furthermore, NR experiments indicate that the (negative) DSPG lipids are associated with lipid extraction upon AuNP adsorption, which is confirmed by coarse-grained MD simulations as a lipid-crawling effect driving further AuNP aggregation. Overall, the obtained detailed molecular view of the interaction mechanisms sheds light on AuNP incorporation and membrane destabilization.

Computational Physics Laboratory Tampere University P O Box 692 FI 33014 Tampere Finland

Department of Physics Norwegian University of Science and Technology NO 7491 Trondheim Norway

Department of Physics University of Helsinki P O Box 64 FI 00014 Helsinki Finland

Institut Laue Langevin 71 Avenue des Martyrs 38042 Grenoble France

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 16610 Prague 6 Czech Republic

Laboratoire TIMC IMAG Université Grenoble Alpes Domaine de la Merci 38706 La Tronche Cedex France

Laboratory of Supramolecular and BioNano Materials Department of Chemistry Materials and Chemical Engineering Politecnico di Milano via Mancinelli 7 20131 Milano Italy

Max Planck Institute of Colloids and Interfaces 14476 Potsdam Germany

MEMPHYS Center for Biomembrane Physics

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