ABSTRACT
Dyneins is an AAA+ motor responsible for motility and force generation towards the minus end of microtubules. Dynein motility is powered by nucleotide-dependent transitions of its linker domain, which transitions between straight (post-powerstroke) and bent (pre-powerstroke) conformations. To understand the dynamics and energetics of the linker, we per-formed all-atom molecular dynamics (MD) simulations of human dynein-2 primed for its power stroke. Simulations re-vealed that the linker can adopt either a bent conformation or a semi-bent conformation, separated by a 5.7 kT energy bar-rier. The linker cannot switch back to its straight conformation in the pre-powerstroke state due to a steric clash with the AAA+ ring. Simulations also showed that an isolated linker has a free energy minimum near the semi-bent conformation in the absence of the AAA+ ring, indicating that the linker stores mechanical energy as it bends and releases this energy during the powerstroke.
Competing Interest Statement
The authors have declared no competing interest.
ABBREVIATIONS
- ATP
- Adenosine triphosphate
- ADP
- Adenosine di-phosphate
- CC
- coiled-coil
- AAA
- ATPases Associated with diverse cellular Activities
- MT
- Microtubule
- MD
- Molecular dynamics
- SMD
- steered molecular dynam-ics
- TMD
- Targeted molecular dynamics
- UMD
- Um-brella sampling molecular dynamics
