Conventional kinesin is a dimeric motor protein that transports membranousorganelles toward the plus-end of microtubules (MTs). Individual kinesin dimersshow steadfast directionality and hundreds of consecutive steps, yetthedetailed physical mechanism remains unclear. Here we compute free energies forthe entire dimer-MT system for all possible interacting configurations bytaking full account of molecular details. Employing merely first principles andseveral measured binding and barrier energies, the system-level analysisreveals insurmountable energy gaps between configurations, asymmetric groundstate caused by mechanically lifted configurational degeneracy, and forbiddentransitions ensuring coordination between both motor domains for alternatingcatalysis. This wealth of physical effects converts a kinesin dimer into amolecular ratchet-and-pawl device, which determinedly locks the dimer'smovement into the MT plus-end and ensures consecutive steps in hand-over-handgait.Under a certain range of extreme loads, however, the ratchet-and-pawldevice becomes defective but not entirely abolished to allow consecutiveback-steps. This study yielded quantitative evidence that kinesin's multiplemolecular properties have been evolutionarily adapted to fine-tune theratchet-and-pawl device so as to ensure the motor's distinguished performance.
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