Studying The Movement Mechanism Of Dimer Kinesin Through Theoretical Modeling And Numerical Simulation

Kinesin is a homodimeric biological molecular motor moving processively on microtubule(MT)filaments through hydrolyzing adenosine triphosphate(ATP)in the cells and plays important roles in intracellular transport and cell division.The key issue in the research of molecular motor is the mechanism of mechanochemical coupling,which is important for the development of biophysics.Since the discovery of kinesin,researchers have studied the movement dynamics of kinesin by using various experimental methods and have obtained a wealth of dynamical results.In order to explain the kinesin's mechanism of movement,researchers built a traditional movement model of kinesin,which proposed that the movement of kinesin is powered by the docking of the neck linker.But the free energy change associated with the neck linker docking is insufficient to provide the energy required for kinesin movement.In addition,it was found experimentally that kinesin can also make a backward movement by hydrolyzing ATP,which can not be explained by the neck linker docking model.Based on the known results of molecular structures,biochemical experiments,and all-atom molecular dynamics simulations,we present a new model.According to the presented model,we conduct detailed simulation about the movement of kinesin by the combination of Brownian dynamics simulation and Monte Carlo simulation.We obtain the following research results.(?)Using the presented model,we conduct the numerical simulation of the movement dynamics of the dimeric kinesin-1.We study the dynamics of dimeric kinesin-1 under different solution viscosity,external loading force,ATP concentration,neck linker length,neck linker docking.The effect of the large-size particle connected to one kinesin head is also studied.The numerical simulation results are consistent with the single-molecule experimental results.Different types of kinesin-1 mutants without and with extensions of the neck linker are computed using a set of parameters,which are consistent with the corresponding experimental data.The backward movement of kinesin-1 mutants with extensions of the neck linker is also explained well.(?)The single-molecule experiments show that kinesin-1 with short stalk limp on the MT,with a marked difference in the mean dwell time of successive steps.The limping factor becomes larger with shorter stalk.We use the presented model to study computationally the asymmetric limping dynamics of kinesin-1.Both the backward longitudinal external forces and the vertical external forces can enhance the limping factor,which are consistent with the experimental results.Our model can explain the molecular mechanism of asymmetric limping dynamics of kinesin-1.We predict that the kinesin mutants with longer neck linker do not exhibit asymmetric limping dynamics.(?)We study computationally the run length of different types of dimeric kinesins(wild types and mutants with longer neck linker)in detail with the presented model.The numerical simulation results are consistent with the experimental data of the run length showing the dramatically asymmetric character to the direction of external forces acting on the bead attached to the stalk.In addition,the simulation data are consistent with the experimental data showing the enhancement of the run length with increasement of phosphate concentration.We provide predicted results of the run length dependence on external force acting on the bead attached to the motor head,which can be tested by the single-molecule experiments in the future.(?)We calculate in detail the dynamics of three different families of kinesins(kinesin-1,kinesin-2,and kinesin-5)according to our presented model.The numerical simulation data of the force dependence of velocity and run length of the three families of kinesins are consistent with the experimental data,both for wild types and mutants with different length of neck linker.The computational studies indicate that kinesin-1,kinesin-2,and kinesin-5 show a much similar mechanism and the different dynamical features are from the different rate constants for chemical reaction and different affinities to the MT.(?)We study computationally the force dependence of the unbinding rate of the kinesin-1 motor according to our presented model.Our calculations show that the kinesin unbinding rates exhibit a non-monotonically increasing characteristic of "slip-catch-slip bond" under backward forces and exhibit a monotonically increasing characteristic of "slip bond" under forward forces.These are consistent with the experimental results from three different experimental groups.Our presented model reveals the origin of the counterintuitive characteristic of "slip-catch-slip bond" under backward forces.The methods using in the research can be extended to the study of the molecular mechanism of other molecular motors.Our presented model and conclusions reveal the kinesin's movement mechanism and can be of significance for studying other molecular motors' mechanochemical coupling mechanism in linear moving tracks.