Department of Physics and Astronomy, Clemson University, Clemson, SC, 29634, USA.
Department of Chemical Engineering, Clemson University, Clemson, SC, 29634, USA.
Sci Rep. 2017 Aug 15;7(1):8237. doi: 10.1038/s41598-017-08419-7.
The ability to predict if a given mutation is disease-causing or not has enormous potential to impact human health. Typically, these predictions are made by assessing the effects of mutation on macromolecular stability and amino acid conservation. Here we report a novel feature: the electrostatic component of the force acting between a kinesin motor domain and tubulin. We demonstrate that changes in the electrostatic component of the binding force are able to discriminate between disease-causing and non-disease-causing mutations found in human kinesin motor domains using the receiver operating characteristic (ROC). Because diseases may originate from multiple effects not related to kinesin-microtubule binding, the prediction rate of 0.843 area under the ROC plot due to the change in magnitude of the electrostatic force alone is remarkable. These results reflect the dependence of kinesin's function on motility along the microtubule, which suggests a precise balance of microtubule binding forces is required.
预测给定突变是否致病具有巨大的潜力，可以影响人类健康。通常，这些预测是通过评估突变对大分子稳定性和氨基酸保守性的影响来进行的。在这里，我们报告了一个新的特征：驱动蛋白马达结构域和微管之间相互作用的静电力分量。我们证明，使用接收者操作特征 (ROC)，结合力的静电力分量的变化能够区分在人类驱动蛋白马达结构域中发现的致病和非致病突变。由于疾病可能源于与驱动蛋白-微管结合无关的多种效应，因此仅由于静电力大小的变化而导致的 ROC 曲线下面积的预测率 0.843 是非常显著的。这些结果反映了驱动蛋白的功能对沿着微管运动的依赖性，这表明需要精确平衡微管结合力。
