Elastic Property of Dynein Motor Domain Obtained from All-Atom Molecular Dynamics Simulations in Explicit Water

Abstract

Dyneins are large microtubule motor proteins that play important roles in various biological processes. Cytoplasmic dynein is responsible for cell division, cell migration and other basic cellular functions. The motor domain of dynein consists of a ring-shaped ATPase hexamer called the AAA+ modules. Recently, ADP-bound high-resolution structures of cytoplasmic dynein have revealed the organization of the motor domain that comprises the AAA+ ring, the linker, stalk/strut and C-sequence (PDB IDs: 3vkh and 3vkg). However, the high-resolution structure of an ATP-bound dynein remains unclear. Here, we built the ATP model from the ADP model, and carried out a molecular dynamics (MD) simulation of both models to investigate the effect of ATP on the structures and dynamics by comparing their trajectories. The higher resolution structure (3vkg), which is a truncation mutant, was chosen. Then, we modeled the missing residues and added the truncated domain from the wild type structure (3vkh). Four ADP molecules were placed at their original positions in the ADP model. The nucleotide in the AAA1 module, which is important for the dynein's function, was replaced from ADP to ATP in the ATP model. A rectangular water box was placed around dynein. We used our new MD program, psygene-G, which utilizes GPGPU for the acceleration of the non-bonded computation. Electrostatic interactions were treated with our zero-dipole summation method. A 200-ns MD simulation for both models revealed that the stalk of the ATP model was more flexible than that of the ADP model. Additional 100-ns simulations starting from the ADP model with ATP ligand and from the ATP model with ADP ligand reproduced this flexibility. The rigidness of both obtained trajectories qualitatively agrees with experimental results.