THEORY OF PROTEIN/PROTEIN ASSOCIATION

蛋白质-蛋白质结合是一系列不同的 包括酶催化/抑制和电子在内的生物过程 运输。形成立体定向结构的定向约束 复杂性严重制约了联想的速度。静电 交互能够弥补这种限制，并增强 速度高达四个数量级。通过一系列 理论和计算研究，首席研究员 最近的研究表明，扩散的静电增强- 受影响的缔合率可以用分子的自由能来预测 形成立体专一性复合体的“过渡态”。建立 这是一种对蛋白质-蛋白质进行真正预测的计算方法 缔合，本文提出的过渡态结构模型 将根据实验结果进行改进和验证 电荷突变和离子强度对几种蛋白质的影响 复合体。其中包括Barnees-Barstar建筑群，该建筑群正在进行中 与英国医学研究委员会的艾伦·费尔什特博士合作 将允许对预测的突变效应进行测试。AS 细胞色素c和细胞色素的应用、结合和解离 C过氧化物酶将被研究，以帮助解决目前关于 电子转移的限速步骤和突变的影响 关于血红蛋白AlphaBeta二聚体组装的速度 定量地确定以解释 杂合子红细胞中正常和变异的血红蛋白。在……上面 在定性层面上，可以预见， 过渡状态将作为理解 单个氨基酸对蛋白质-蛋白质结合的贡献。

Protein-protein association is a central event in a diverse range of biological processes including enzyme catalysis/inhibition and electron transport. The orientational constraints for forming a stereospecific complex severely restrict the rate of association. Electrostatic interactions are able to compensate for such restriction and enhance the rate by as much as four orders of magnitude. Through a series of theoretical and computational studies, the principal investigator recently has shown that the electrostatic enhancement of the diffusion- influenced association rate can be predicted by the free energy of a "transition state" for forming the stereospecific complex. To establish this as a truly predictive computational approach to protein-protein association, a structural model for the transition state proposed herein will be refined and validated against experimental results for the effects of charge mutations and ionic strength on several protein complexes. These include the barnaes-barstar complex, on which ongoing collaboration with Dr. Alan Fersht of the UK Medical Research Council will allow for predicted mutational effects to be tested. As applications, association and dissociation of cytochrome c and cytchrome c peroxidase will be studied to help settle the current debate about the rate-limiting step for electron transfer and the effects of mutations on the rate of hemoglobin AlphaBeta dimer assembly will be quantitatively determined to account for the relative proportions of normal and variant hemoglobins in red blood cells of heterozygotes. On a qualitative level, it is envisioned that the structural model for the transition state will serve as a guide for understanding the contributions of individual amino acids to protein-protein association.