Schluttig Jakob, Alamanova Denitsa, Helms Volkhard, Schwarz Ulrich S
University of Heidelberg, Bioquant 0013, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
J Chem Phys. 2008 Oct 21;129(15):155106. doi: 10.1063/1.2996082.
We study the formation of protein-protein encounter complexes with a Langevin equation approach that considers direct, steric, and thermal forces. As three model systems with distinctly different properties we consider the pairs barnase:barstar, cytochrome c-cytochrome c peroxidase, and p53:MDM2. In each case, proteins are modeled either as spherical particles, as dipolar spheres, or as collection of several small beads with one dipole. Spherical reaction patches are placed on the model proteins according to the known experimental structures of the protein complexes. In the computer simulations, concentration is varied by changing box size. Encounter is defined as overlap of the reaction patches and the corresponding first passage times are recorded together with the number of unsuccessful contacts before encounter. We find that encounter frequency scales linearly with protein concentration, thus proving that our microscopic model results in a well-defined macroscopic encounter rate. The number of unsuccessful contacts before encounter decreases with increasing encounter rate and ranges from 20 to 9000. For all three models, encounter rates are obtained within one order of magnitude of the experimentally measured association rates. Electrostatic steering enhances association up to 50-fold. If diffusional encounter is dominant (p53:MDM2) or similarly important as electrostatic steering (barnase:barstar), then encounter rate decreases with decreasing patch radius. More detailed modeling of protein shapes decreases encounter rates by 5%-95%. Our study shows how generic principles of protein-protein association are modulated by molecular features of the systems under consideration. Moreover it allows us to assess different coarse-graining strategies for the future modeling of the dynamics of large protein complexes.
我们采用朗之万方程方法研究蛋白质 - 蛋白质相遇复合物的形成，该方法考虑了直接力、空间力和热力。作为具有明显不同性质的三个模型系统，我们考虑巴那斯酶：巴那斯塔、细胞色素c - 细胞色素c过氧化物酶以及p53：MDM2这几对。在每种情况下，蛋白质要么被建模为球形颗粒，要么为偶极球体，或者是带有一个偶极的几个小珠子的集合。根据蛋白质复合物已知的实验结构，在模型蛋白质上放置球形反应区域。在计算机模拟中，通过改变盒子大小来改变浓度。相遇被定义为反应区域的重叠，并记录相应的首次通过时间以及相遇前不成功接触的次数。我们发现相遇频率与蛋白质浓度呈线性关系，从而证明我们的微观模型得出了明确的宏观相遇速率。相遇前不成功接触的次数随着相遇速率的增加而减少，范围从20到9000。对于所有这三个模型，相遇速率在实验测量的缔合速率的一个数量级范围内获得。静电引导可将缔合增强多达50倍。如果扩散相遇占主导（p53：MDM2）或与静电引导同样重要（巴那斯酶：巴那斯塔），那么相遇速率会随着反应区域半径的减小而降低。对蛋白质形状进行更详细的建模会使相遇速率降低5% - 95%。我们的研究展示了所考虑系统的分子特征如何调节蛋白质 - 蛋白质缔合的通用原理。此外，它使我们能够评估用于未来大型蛋白质复合物动力学建模的不同粗粒化策略。
