Propofol is a widely used general anesthetic to induce and maintain anesthesia, and its effects are thought to occur through impact on the ligand-gated channels including the GABA_A receptor. Propofol also interacts with a large number of proteins including molecular motors and inhibits kinesin processivity, resulting in significant decrease in the run length for conventional kinesin-1 and kinesin-2. However, the molecular mechanism by which propofol achieves this outcome is not known. The structural transition in the kinesin neck-linker region is crucial for its processivity. In this study, we analyzed the effect of propofol and its fluorine derivative (fropofol) on the transition in the neck-linker region of kinesin. Propofol binds at two crucial surfaces in the leading head: one at the microtubule-binding interface and the other in the neck-linker region. We observed in both the cases the order–disorder transition of the neck-linker was disrupted and kinesin lost its signal for forward movement. In contrast, there was not an effect on the neck-linker transition with propofol binding at the trailing head. Free-energy calculations show that propofol at the microtubule-binding surface significantly reduces the microtubule-binding affinity of the kinesin head. While propofol makes pi–pi stacking and H-bond interactions with the propofol binding cavity, fropofol is unable to make a suitable interaction at this binding surface. Therefore, the binding affinity of fropofol is much lower compared to propofol. Hence, this study provides a mechanism by which propofol disrupts kinesin processivity and identifies transitions in the ATPase stepping cycle likely affected.

异丙酚是一种广泛使用的诱导和维持麻醉的全身麻醉剂，其作用被认为是通过影响包括GABA _A在内的配体门控通道而发生_的受体。异丙酚还与包括分子马达在内的大量蛋白质相互作用，并抑制驱动蛋白的持续合成能力，从而导致常规驱动蛋白1和驱动蛋白2的运行长度显着减少。但是，异丙酚达到此结果的分子机制尚不清楚。驱动蛋白颈连接区中的结构转变对其持续性至关重要。在这项研究中，我们分析了异丙酚及其氟衍生物（ropofofol）对驱动蛋白颈连接区过渡的影响。异丙酚在前导头的两个关键表面上结合：一个在微管结合界面处，另一个在颈部接头区域中。在这两种情况下，我们都观察到颈连接器的有序-无序过渡被破坏，驱动蛋白失去了向前运动的信号。相反，异丙酚在尾端结合，对颈部连接物的转变没有影响。自由能计算表明，在微管结合表面的异丙酚显着降低了驱动蛋白头的微管结合亲和力。尽管丙泊酚与丙泊酚结合腔进行pi-pi堆积和H键相互作用，但氟泊酚无法在该结合表面进行合适的相互作用。因此，与丙泊酚相比，丙泊酚的结合亲和力要低得多。因此，这项研究提供了一种机制，丙泊酚可通过该机制破坏驱动蛋白的持续合成能力，并确定可能受影响的ATPase步进循环的转变。自由能计算表明，在微管结合表面的异丙酚显着降低了驱动蛋白头的微管结合亲和力。尽管丙泊酚与丙泊酚结合腔进行pi-pi堆积和H键相互作用，但氟泊酚无法在该结合表面进行合适的相互作用。因此，与丙泊酚相比，丙泊酚的结合亲和力要低得多。因此，这项研究提供了一种机制，丙泊酚可通过该机制破坏驱动蛋白的持续合成能力，并确定可能受影响的ATPase步进循环的转变。自由能计算表明，在微管结合表面的异丙酚显着降低了驱动蛋白头的微管结合亲和力。尽管丙泊酚与丙泊酚结合腔进行pi-pi堆积和H键相互作用，但氟泊酚无法在该结合表面进行合适的相互作用。因此，与丙泊酚相比，丙泊酚的结合亲和力要低得多。因此，这项研究提供了一种机制，丙泊酚可通过该机制破坏驱动蛋白的持续合成能力，并确定可能受影响的ATPase步进循环的转变。