Mechanism for the Rare Fluctuation That Powers Protein Conformational Change

Most functional processes of biomolecules are rare events. Key to a rare event is the rare fluctuation that enables the energy activation process that precedes and powers crossing of the activation barrier. However, the physical nature of this rare fluctuation and how it enables energy activation and subsequently barrier crossing are unknown. We developed a novel metric, the reaction capacity p, that rigorously defines the beginning and parameterizes the progress of energy activation. This enabled us to identify the rare fluctuation as a special phase-space condition that is necessary and sufficient for initiating systematic energy flow from the non-reaction coordinates into the reaction coordinates. The energy activation of a prototype biomolecular isomerization reaction is dominated by kinetic energy transferring into and accumulating in the reaction coordinates, administered by inertial forces alone. This mechanism for energy activation is fundamentally different from the mechanism suggested by Kramers theory.