Steered Molecular Dynamics Simulation of Kinesin Detachment from the Microtubule Surface and the Effect of 1,3-Dinitrobenzene

Abstract

Experimental evidence has shown that kinesin transport of organelles involves distinct attachment / detachment events from the microtubule (MT) surface. Steered molecular dynamics (SMD) simulations were employed to investigate kinesin detachment from the MT surface. Simulation results show that reducing the pulling speed, or using a softer pulling spring constant, yields better agreement between SMD simulations and experimental detachment force measurements. Different detachment pathways were observed, depending upon the parametric conditions at which SMD simulation is performed. Detachment of kinesin from a MT surface in which the tubulin dimer is kept rigid required higher detachment force at all pulling conditions, compared with the force when only the two ends of dimer were fixed. Kinesin detachment from the tubulin dimer with fixed ends involves rearrangement of the switch II region, the main kinesin-microtubule binding element, in a rotational direction opposite the rest of the kinesin head. This result agrees with experimental evidence showing that rearrangement of the switch II region is required for detachment of kinesin from the MT surface.Preliminary data suggest astrocytes are more vulnerable to attack by neurotoxicants such as 1,3-dinitrobenzene (DNB) than their neuronal counterparts, suggesting that short-term loss of astrocytes in affected regions may be a neuroprotective rather than pathologic response. Despite advances in determination of selective cellular vulnerability to DNB, the mechanisms governing interplay between astrocytes and neurons remain unclear. Increasing damage to astrocyte mitochondria may contribute to decreased neuroprotection during aging. Molecular modeling was used to investigate the possible intervention of DNB on kinesin-MT detachment. DNB was found to bind within the interface between kinesin and the tubulin dimer. SMD simulations of kinesin detachment from the kinesin-MT complex in the presence of DNB binding are presented and discussed.