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Protein-protein association: Investigation of factors influencingassociation rates by Brownian dynamics simulations

机译：蛋白质-蛋白质缔合：通过布朗动力学模拟研究影响缔合率的因素

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摘要

The rate of protein-protein association limits the response time due to protein-protein interactions. The bimolecular association rate may be diffusion-controlled or influenced, and in such cases, Brownian dynamics simulations of protein-protein diffusional association may be used to compute association rates. Here, we report Brownian dynamics simulations of the diffusional association of five different protein-protein pairs: barnase and barstar, acetylcholinesterase and fasciculin-2, cytochrome c peroxidase and cytochrome c, the HyHEL-5 antibody and hen egg lysozyme (HEL), and the HyHEL-10 antibody and HEL. The same protocol was used to compute the diffusional association rates for all the protein pairs in order to assess, by comparison to experimentally measured rates, whether the association of these proteins can be explained solely on the basis of diffusional encounter. The simulation protocol is similar to those previously derived for simulation of the association of barnase and barstar, and of acetylcholinesterase and fasciculin-2; these produced results in excellent agreement with experimental data for these protein pairs, with changes in association rate due to mutations reproduced within the limits of expected computational and modeling errors. Here, we find that for all protein pairs, the effects of mutations can be well reproduced by the simulations, even though the degree of the electrostatic translational and orientational steering varies widely between the cases. However, the absolute values of association rates for the acetylcholinesterase: fasciculin-2 and HyHEL-10 antibody: HEL pairs are overestimated. Comparison of bound and unbound protein structures shows that this may be due to gating resulting from protein flexibility in some of the proteins. This may lower the association rates compared to their bimolecular diffusional encounter rates.
机译：蛋白质-蛋白质缔合的速率由于蛋白质-蛋白质相互作用而限制了响应时间。双分子缔合速率可以受扩散控制或影响，在这种情况下，蛋白质-蛋白质扩散缔合的布朗动力学模拟可用于计算缔合速率。在这里，我们报告了五个不同蛋白质-蛋白质对的扩散关联的布朗动力学模拟：barnase和barstar，乙酰胆碱酯酶和fasciculin-2，细胞色素c过氧化物酶和细胞色素c，HyHEL-5抗体和鸡蛋溶菌酶（HEL），以及HyHEL-10抗体和HEL。使用相同的协议来计算所有蛋白质对的扩散缔合速率，以便通过与实验测得的速率进行比较来评估这些蛋白质的缔合是否可以仅基于扩散相遇来解释。该模拟方案与先前推导的针对barnase和barstar以及乙酰胆碱酯酶和fasciculin-2的缔合的模拟方案相似。这些产生的结果与这些蛋白质对的实验数据非常吻合，并且由于在预期的计算和建模误差的范围内复制的突变导致缔合率发生变化。在这里，我们发现，对于所有蛋白质对，通过模拟可以很好地再现突变的影响，即使静电平移和方向操纵的程度在两种情况之间变化很大。但是，乙酰胆碱酯酶：fasciculin-2和HyHEL-10抗体：HEL对的缔合速率的绝对值被高估了。结合的和未结合的蛋白质结构的比较表明，这可能是由于某些蛋白质的蛋白质柔韧性导致的门控。与它们的双分子扩散相遇率相比，这可以降低缔合率。

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