Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.
Department of Bioengineering, Rice University, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8611-E8617. doi: 10.1073/pnas.1710328114. Epub 2017 Sep 27.
Motor proteins are active enzymatic molecules that support important cellular processes by transforming chemical energy into mechanical work. Although the structures and chemomechanical cycles of motor proteins have been extensively investigated, the sensitivity of a motor's velocity in response to a force is not well-understood. For kinesin, velocity is weakly influenced by a small to midrange external force (weak susceptibility) but is steeply reduced by a large force. Here, we utilize a structure-based molecular dynamic simulation to study the molecular origin of the weak susceptibility for a single kinesin. We show that the key step in controlling the velocity of a single kinesin under an external force is the ATP release from the microtubule-bound head. Only under large loading forces can the motor head release ATP at a fast rate, which significantly reduces the velocity of kinesin. It underpins the weak susceptibility that the velocity will not change at small to midrange forces. The molecular origin of this velocity reduction is that the neck linker of a kinesin only detaches from the motor head when pulled by a large force. This prompts the ATP binding site to adopt an open state, favoring ATP release and reducing the velocity. Furthermore, we show that two load-bearing kinesins are incapable of equally sharing the load unless they are very close to each other. As a consequence of the weak susceptibility, the trailing kinesin faces the challenge of catching up to the leading one, which accounts for experimentally observed weak cooperativity of kinesins motors.
马达蛋白是一种具有活性的酶分子，通过将化学能转化为机械能来支持重要的细胞过程。尽管马达蛋白的结构和化学机械循环已经得到了广泛的研究，但马达速度对力的敏感性还没有得到很好的理解。对于驱动蛋白来说，速度对小到中等范围的外力（弱敏感性）的影响较弱，但对大的力的影响则急剧降低。在这里，我们利用基于结构的分子动力学模拟来研究单个驱动蛋白弱敏感性的分子起源。我们表明，控制单个驱动蛋白在外部力下速度的关键步骤是 ATP 从微管结合头部的释放。只有在较大的加载力下，马达头部才能以较快的速度释放 ATP，这显著降低了驱动蛋白的速度。这解释了为什么在小到中等范围内的力作用下，速度不会发生变化，这就是弱敏感性的原因。这种速度降低的分子起源是，驱动蛋白的颈环连接只有在受到大的力时才会从马达头部脱离。这促使 ATP 结合位点采用开放状态，有利于 ATP 的释放，从而降低速度。此外，我们还表明，除非两个承载负荷的驱动蛋白非常接近，否则它们无法平等地分担负荷。由于弱敏感性，尾随的驱动蛋白面临着追赶领先的驱动蛋白的挑战，这解释了实验观察到的驱动蛋白马达弱协同性的原因。
