Keskin Ozlem
Koc University, Center for Computational Biology and Bioinformatics and College of Engineering, Rumeli Feneri Yolu, Sariyer, Istanbul, Turkey.
BMC Struct Biol. 2007 May 17;7:31. doi: 10.1186/1472-6807-7-31.
How antibodies recognize and bind to antigens can not be totally explained by rigid shape and electrostatic complimentarity models. Alternatively, pre-existing equilibrium hypothesis states that the native state of an antibody is not defined by a single rigid conformation but instead with an ensemble of similar conformations that co-exist at equilibrium. Antigens bind to one of the preferred conformations making this conformation more abundant shifting the equilibrium.
Here, two antibodies, a germline antibody of 36-65 Fab and a monoclonal antibody, SPE7 are studied in detail to elucidate the mechanism of antibody-antigen recognition and to understand how a single antibody recognizes different antigens. An elastic network model, Anisotropic Network Model (ANM) is used in the calculations. Pre-existing equilibrium is not restricted to apply to antibodies. Intrinsic fluctuations of eight proteins, from different classes of proteins, such as enzymes, binding and transport proteins are investigated to test the suitability of the method. The intrinsic fluctuations are compared with the experimentally observed ligand induced conformational changes of these proteins. The results show that the intrinsic fluctuations obtained by theoretical methods correlate with structural changes observed when a ligand is bound to the protein. The decomposition of the total fluctuations serves to identify the different individual modes of motion, ranging from the most cooperative ones involving the overall structure, to the most localized ones.
Results suggest that the pre-equilibrium concept holds for antibodies and the promiscuity of antibodies can also be explained this hypothesis: a limited number of conformational states driven by intrinsic motions of an antibody might be adequate to bind to different antigens.
抗体如何识别并结合抗原，无法完全用刚性形状和静电互补模型来解释。另外，预先存在的平衡假说指出，抗体的天然状态并非由单一刚性构象定义，而是由一组在平衡状态下共存的相似构象定义。抗原与其中一种优选构象结合，使该构象更为丰富，从而改变平衡。
本文详细研究了两种抗体，一种是36-65 Fab的胚系抗体，另一种是单克隆抗体SPE7，以阐明抗体-抗原识别机制，并了解单一抗体如何识别不同抗原。计算中使用了弹性网络模型，即各向异性网络模型（ANM）。预先存在的平衡并不局限于应用于抗体。研究了来自不同类别的蛋白质（如酶、结合蛋白和转运蛋白）的8种蛋白质的内在波动，以测试该方法的适用性。将内在波动与实验观察到的这些蛋白质的配体诱导构象变化进行比较。结果表明，通过理论方法获得的内在波动与配体结合到蛋白质时观察到的结构变化相关。总波动的分解有助于识别不同的个体运动模式，从涉及整体结构的最协同模式到最局部模式。
结果表明，预平衡概念适用于抗体，抗体的多特异性也可以用该假说来解释：由抗体的内在运动驱动的有限数量的构象状态可能足以结合不同的抗原。
