Functional Modes and Residue Flexibility Control the Anisotropic Response of Guanylate Kinase to Mechanical Stress
Functional Modes and Residue Flexibility Control the Anisotropic Response of Guanylate Kinase to Mechanical Stress
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DOI：
10.1016/j.bpj.2010.09.026
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发表时间：
2010-11-17
影响因子：
3.4
通讯作者：
Baaden, Marc
中科院分区：
文献类型：
--
作者：
Sacquin-Mora, Sophie;Delalande, Olivier;Baaden, Marc
酶的机械性能和生物活性之间的耦合是一个公认的特征，已经成为许多实验和理论工作的目标。特别是，最近的实验表明，机械应力可以各向异性地调制酶的功能。我们使用一种研究残基尺度上局部灵活性的方法来研究这种现象，该方法结合了简化的蛋白质表示和布朗动力学模拟。我们对鸟苷酸激酶酶进行了计算，以研究其在受到各向异性变形时的力学响应。由此引起的蛋白质刚性分布的改变可能与实验观察到的底物结合亲和力的变化有关。对运动轨迹的主成分的进一步分析表明，对蛋白质施加机械约束可以破坏其动力学，从而导致酶的催化速率降低。最终，对蛋白质表面的系统探测导致了对潜在热点的预测，在这些热点中，从力学和动力学的角度来看，施加外部约束将产生巨大的功能响应。这种酶工程方法打开了通过改变选定的外力来调节催化功能的可能性。
The coupling between the mechanical properties of enzymes and their biological activity is a well-established feature that has been the object of numerous experimental and theoretical works. In particular, recent experiments show that enzymatic function can be modulated anisotropically by mechanical stress. We study such phenomena using a method for investigating local flexibility on the residue scale that combines a reduced protein representation with Brownian dynamics simulations. We performed calculations on the enzyme guanylate kinase to study its mechanical response when submitted to anisotropic deformations. The resulting modifications of the protein's rigidity profile can be related to the changes in substrate binding affinity observed experimentally. Further analysis of the principal components of motion of the trajectories shows how the application of a mechanical constraint on the protein can disrupt its dynamics, thus leading to a decrease of the enzyme's catalytic rate. Eventually, a systematic probe of the protein surface led to the prediction of potential hotspots where the application of an external constraint would produce a large functional response both from the mechanical and dynamical points of view. Such enzyme-engineering approaches open the possibility to tune catalytic function by varying selected external forces.