Sandak B, Wolfson H J, Nussinov R
Department of Applied Mathematics and Computer Science, Weizmann Institute of Science, Rehovot, Israel.
Proteins. 1998 Aug 1;32(2):159-74.
Here we dock a ligand onto a receptor surface allowing hinge-bending domain/substructural movements. Our approach mimics and manifests induced fit in molecular recognition. All angular rotations are allowed on the one hand, while a conformational space search is avoided on the other. Rather than dock each of the molecular parts separately with subsequent reconstruction of the consistently docked molecules, all parts are docked simultaneously while still utilizing the position of the hinge from the start. Like pliers closing on a screw, the receptor automatically closes on its ligand in the best surface-matching way. Movements are allowed either in the ligand or in the larger receptor, hence reproducing induced molecular fit. Hinge bending movements are frequently observed when molecules associate. There are numerous examples of open versus closed conformations taking place upon binding. Such movements are observed when the substrate binds to its respective enzyme. In particular, such movements are of interest in allosteric enzymes. The movements can involve entire domains, subdomains, loops, (other) secondary structure elements, or between any groups of atoms connected by flexible joints. We have implemented the hinges at points and at bonds. By allowing 3-dimensional (3-D) rotation at the hinge, several rotations about (consecutive or nearby) bonds are implicitly taken into account. Alternatively, if required, the point rotation can be restricted to bond rotation. Here we illustrate this hinge-bending docking approach and the insight into flexibility it provides on a complex of the calmodulin with its M13 ligand, positioning the hinges either in the ligand or in the larger receptor. This automated and efficient method is adapted from computer vision and robotics. It enables utilizing entire molecular surfaces rather than focusing a priori on active sites. Hence, allows attaining the overall optimally matching surfaces, the extent and type of motions which are involved. Here we do not treat the conformational flexibility of side-chains or of very small pieces of the molecules. Therefore, currently available methods addressing these issues and the method presented here, are complementary to each other, expanding the repertoire of computational docking tools foreseen to aid in studies of recognition, conformational flexibility and drug design.
在这里，我们将一个配体对接至受体表面，允许铰链弯曲结构域/亚结构移动。我们的方法模拟并体现了分子识别中的诱导契合。一方面允许所有角度旋转，另一方面避免构象空间搜索。不是分别对接每个分子部分，随后再重建一致对接的分子，而是所有部分同时对接，同时从一开始就利用铰链的位置。就像钳子夹住螺丝一样，受体以最佳的表面匹配方式自动夹住其配体。允许在配体或更大的受体中移动，从而再现诱导分子契合。当分子结合时，经常会观察到铰链弯曲运动。有许多结合时开放与闭合构象的例子。当底物与其相应的酶结合时会观察到这种运动。特别是，这种运动在变构酶中很受关注。这些运动可能涉及整个结构域、亚结构域、环、（其他）二级结构元件，或通过柔性接头连接的任何原子组之间。我们已在点和键处实现了铰链。通过允许在铰链处进行三维（3-D）旋转，隐含地考虑了围绕（连续或相邻）键的几次旋转。或者，如果需要，点旋转可以限制为键旋转。在这里，我们说明了这种铰链弯曲对接方法及其对钙调蛋白与其M13配体复合物灵活性的洞察，将铰链定位在配体或更大的受体中。这种自动化且高效的方法改编自计算机视觉和机器人技术。它能够利用整个分子表面，而不是先验地聚焦于活性位点。因此，可以实现整体最佳匹配的表面、所涉及的运动范围和类型。在这里，我们不处理侧链或分子非常小的片段的构象灵活性。因此，目前解决这些问题的可用方法与这里提出的方法相互补充，扩展了预计有助于识别、构象灵活性和药物设计研究的计算对接工具库。
