Coarse-grained modeling of the structural states and transition underlying the powerstroke of dynein motor domain

This study aims to model a minimal dynein motor domain capable of motor function, which consists of the linker domain, six AAA+ modules (AAA1-AAA6), coiled coil stalk, and C-terminus domain. To this end, we have used the newly solved X-ray structures of dynein motor domain to perform a coarse-grained modeling of dynein's post-and pre-powerstroke conformation and the conformational transition between them. First, we have used normal mode analysis to identify a single normal mode that captures the coupled motions of AAA1-AAA2 closing and linker domain rotation, which enables the ATP-driven recovery stroke of dynein. Second, based on the post-powerstroke conformation solved crystallographically, we have modeled dynein's pre-powerstroke conformation by computationally inducing AAA1-AAA2 closing and sliding of coiled coil stalk, and the resulting model features a linker domain near the pre-powerstroke position and a slightly tilted stalk. Third, we have modeled the conformational transition from pre- to post-powerstroke conformation, which predicts a clear sequence of structural events that couple microtubule binding, powerstroke and product release, and supports a signaling path from stalk to AAA1 via AAA3 and AAA4. Finally, we have found that a closed AAA3-AAA4 interface (compatible with nucleotide binding) is essential to the mechanochemical coupling in dynein. Our modeling not only offers unprecedented structural insights to the motor function of dynein as described by past single-molecule, fluorescence resonance energy transfer, and electron microscopy studies, but also provides new predictions for future experiments to test. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4704661]