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Lipid membrane fusion is critical to cellular transport and signaling processes such as constitutive secretion, neurotransmitter release, and infection by enveloped viruses. Here, we introduce a powerful computational methodology for simulating membrane fusion from a starting configuration designed to approximate activated prefusion assemblies from neuronal and viral fusion, producing results on a time scale and degree of mechanistic detail not previously possible to our knowledge. We use an approach to the long time scale simulation of fusion by constructing a Markovian state model with large-scale distributed computing, yielding an understanding of fusion mechanisms on time scales previously impossible to simulate to our knowledge. Our simulation data suggest a branched pathway for fusion, in which a common stalk-like intermediate can either rapidly form a fusion pore or remain in a metastable …