KINETICS OF PROTEIN PROTEIN ASSOCIATION EXPLAINED BY BROWNIAN DYNAMICS COMPUTER-SIMULATION
KINETICS OF PROTEIN PROTEIN ASSOCIATION EXPLAINED BY BROWNIAN DYNAMICS COMPUTER-SIMULATION
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DOI：
10.1073/pnas.89.8.3338
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发表时间：
1992-04-15
影响因子：
11.1
通讯作者：
ERICKSON, HP
中科院分区：
文献类型：
--
作者：
NORTHRUP, SH;ERICKSON, HP
蛋白质-蛋白质键的形成，例如抗体-抗原络合或蛋白质单体聚集成二聚体和更大的聚集体，双分子速率常数约为 10(6) M-1.s-1，仅比扩散限制的 Smoluchowski 速率慢 3 个数量级。然而，由于蛋白质-蛋白质键需要旋转排列在几埃的公差范围内，纯几何估计表明观察到的速率可能比 Smoluchowski 速率低 6 个数量级。先前的理论处理尚未解决蛋白质-蛋白质关联的高度特异性对接标准——整个亚基界面必须在正确位置的 2 埃内对齐。一些研究表明，单独的扩散不能产生快速缔合动力学，并假设“长时间碰撞”和/或静电或疏水转向力的作用来加速缔合。在本研究中，布朗动力学模拟方法用于计算中性球形模型蛋白质与规定的对接标准的关联率。布朗模拟预测这种通用蛋白质-蛋白质关联的速率为 2 x 10(6) M-1.s-1，该速率比最简单的几何计算预测的速率快 2000 倍，并且基本上等于在水溶液中观察到的蛋白质-蛋白质关联的速率。这种高速率是通过简单的扩散过程获得的，并且不需要任何超出部分形成的粘合所实现的吸引力或转向力。速率的提高归因于扩散捕获效应，其中被水包围和捕获的蛋白质对在每次相遇期间经历多次碰撞和旋转重新定向。
Protein-protein bond formations, such as antibody-antigen complexation or aggregation of protein monomers into dimers and larger aggregates, occur with bimolecular rate constants on the order of 10(6) M-1.s-1, which is only 3 orders of magnitude slower than the diffusion-limited Smoluchowski rate. However, since the protein-protein bond requireS rotational alignment to within a few angstroms of tolerance, purely geometric estimates would suggest that the observed rates might be 6 orders of magnitude below the Smoluchowski rate. Previous theoretical treatments have not been, solved for the highly specific docking criteria of protein-protein association-the entire subunit interface must be aligned within 2 angstrom of the correct position. Several studies have suggested that diffusion alone could not produce the rapid association kinetics and have postulated "lengthy collisions" and/or the operation of electrostatic or hydrophobic steering forces to accelerate the association. In the present study, the Brownian dynamics simulation method is used to compute the rate of association of neutral spherical model proteins with the stated docking criteria. The Brownian simulation predicts a rate of 2 x 10(6) M-1.s-1 for this generic protein-protein association, a rate that is 2000 times faster than that predicted by the simplest geometric calculation and is essentially equal to the rates observed for protein-protein association in aqueous solution. This high rate is obtained by simple diffusive processes and does not require any attractive or steering forces beyond those achieved for a partially formed bond. The rate enhancement is attributed to a diffusive entrapment effect, in which a protein pair surrounded and trapped by water undergoes multiple collisions with rotational reorientation during each encounter.