Northrup S H, Luton J A, Boles J O, Reynolds J C
Department of Chemistry, Tennessee Technological University, Cookeville 38505.
J Comput Aided Mol Des. 1988 Jan;1(4):291-311. doi: 10.1007/BF01677278.
The Brownian Dynamics (BD) method is applied to study the diffusive dynamics and interaction of two proteins, cytochrome c (CYTC) and cytochrome c peroxidase (CYP). We examine the role of protein electrostatic charge distribution in the facilitation of protein-protein docking prior to the electron transfer step, assessing the influence of individual charged amino acid residues. Accurate interaction potentials are computed by iterating the linearized Poisson-Boltzmann (PB) equation around the larger protein CYP. The low dielectric constant inside proteins, electrolyte screening effects and irregular protein surface topography are taken into account. We observe a large ensemble of electrostatically stable encounter complexes seemingly with acceptable geometric requirements for electron transfer rather than a single dominant complex. Stabilities of the large variety of docking complexes are rationalized in terms of generalized charged residue complementarities. However, it is found that the electrostatic interactions giving rise to complex stabilities are somewhat nonspecific in nature. A large series of additional simulations are performed in which individual charged residues on CYTC have been chemically modified. Resulting perturbations of the association rate are significant and qualitatively similar to results observed in comparable kinetics experiments. We therefore demonstrate the potential of the Brownian dynamics method to estimate the effects of site-directed mutagenesis on protein-protein and protein-ligand diffusional association rates.
采用布朗动力学（BD）方法研究了两种蛋白质，即细胞色素c（CYTC）和细胞色素c过氧化物酶（CYP）的扩散动力学及相互作用。我们研究了蛋白质静电电荷分布在电子转移步骤之前促进蛋白质 - 蛋白质对接过程中的作用，评估了单个带电氨基酸残基的影响。通过在较大的蛋白质CYP周围迭代线性化泊松 - 玻尔兹曼（PB）方程来计算精确的相互作用势。考虑了蛋白质内部的低介电常数、电解质屏蔽效应以及不规则的蛋白质表面形貌。我们观察到大量静电稳定的相遇复合物，其似乎具有可接受的电子转移几何要求，而不是单一的主导复合物。根据广义带电残基互补性对多种对接复合物的稳定性进行了合理化解释。然而，发现导致复合物稳定性的静电相互作用在本质上有些非特异性。进行了一系列额外的模拟，其中CYTC上的单个带电残基被化学修饰。由此产生的缔合速率扰动是显著的，并且在定性上与在可比动力学实验中观察到的结果相似。因此，我们证明了布朗动力学方法在估计定点诱变对蛋白质 - 蛋白质和蛋白质 - 配体扩散缔合速率影响方面的潜力。
