Many important cellular functions are performed by membrane proteins, and in particular by association of proteins via transmembrane helices. However, the mechanism of how the helices associate has been challenging to study, by either experiment or simulation. Here, we use advanced molecular simulation methods to overcome the slow time scales involved in helix association and dissociation and obtain a view of the association mechanism in atomic detail. We show that association occurs via an initially non-native dimer, before proceeding to the native state, and we validate our results by comparison to available experimental kinetic data. Our methods will also aid in the study of the assembly mechanism of larger transmembrane proteins via molecular simulation.
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