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Molecular Dynamics Simulations of Lipid Vesicle Fusion in Atomic Detail

Volker Knecht ^* and Siewert-Jan Marrink 

^* Max Planck Institute of Colloids and Interfaces, Potsdam, Germany; and Groningen Biomolecular Sciences and Biotechnology Institute, Department of Biophysical Chemistry, University of Groningen, Nijenborgh, Groningen, The Netherlands

Correspondence: Address reprint requests and inquiries to Siewert-Jan Marrink, Tel: 31-50-363-4457; E-mail: s.j.marrink{at}rug.nl.

The fusion of a membrane-bounded vesicle with a target membrane is a key step in intracellular trafficking, exocytosis, and drug delivery. Molecular dynamics simulations have been used to study the fusion of small unilamellar vesicles composed of a dipalmitoyl-phosphatidylcholine (DPPC)/palmitic acid 1:2 mixture in atomic detail. The simulations were performed at 350–370 K and mimicked the temperature- and pH-induced fusion of DPPC/palmitic acid vesicles from experiments by others. To make the calculations computationally feasible, a vesicle simulated at periodic boundary conditions was fused with its periodic image. Starting from a preformed stalk between the outer leaflets of the vesicle and its periodic image, a hemifused state formed within 2 ns. In one out of six simulations, a transient pore formed close to the stalk, resulting in the mixing of DPPC lipids between the outer and the inner leaflet. The hemifused state was (meta)stable on a timescale of up to 11 ns. Forcing a single lipid into the interior of the hemifusion diaphragm induced the formation and expansion of a fusion pore on a nanosecond timescale. This work opens the perspective to study a wide variety of mesoscopic biological processes in atomic detail.

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