Proper intracellular transport and organization is of utmost importance for eukaryotic cells to function in a healthy manner. Intracellular transport and organization is carried out by motor proteins which walk along cell actin filaments and microtubules (MT). Motor proteins carry vesicles and organelles effectively along the cytoplasm by taking hundreds of consecutive steps, reaching speeds of micrometers/second orders. Transport on MTs can be into two directions: Towards the - or + ends of the MTs. Transport in the – direction is conducted by cytoplasmic dyneins, which are capable of carrying a variety of cargos. Disorders/irregularities in cytoplasmic dinein function were shown to be associated with neurodegenerative diseases, including amyotrophic lateral sclerosis, Charcot-Marie-Tooth, Alzheimer's, Parkinson's and Huntington's, and also with lissencephaly and ciliary dyskinesia. This close relationship necessitates; especially if new therapeutic strategies are considered; understanding how the cytoplasmic dynein motor proteins operate and what type of functional malfunction takes place that cause those diseases.
Cytoplasmic dynein is a homodimeric AAA+ motor consisting of two identical micro-molecular machines structurally connected to each other. Each of these machines comprise a hexameric ring shaped catalytic domain (head) that converts chemical energy ( free energy output from adenosine triphosphate (ATP) hydrolysis) into work. There are two arms connected to the ring. One of those arms, named linker, is considered to be the mechanical element of dynein motion; Energy from the ATP hydrolysis is used to move the linker and, by doing so, the work required to move dynein along the microtubule is produced. However, the details of this mechanism; features such as inter-regional energy transfer, energy conversion, bonds created and broken during the movement, and regulation mechanism is not well understood. By using advanced Molecular Dynamics (MD) simulation techniques, Statistical Thermodynamics and Physics , we are aiming to perform a comprehensive investigation of the mechanochemical cycle of cytoplasmic dyneins and provide the literature with unique information on its underlying mechanism.
Figure 1. Mechanochemical cycle of dynein. (Can, S., Lacey, S., Gur, M., Carter, A. P.,Yildiz, A. (2019). Directionality of dynein is controlled by the angle and length of its stalk. Nature, 566(7744), 407)