Electrostatic specificity in molecular ligand design
Electrostatic specificity in molecular ligand design
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DOI：
10.1063/1.481522
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发表时间：
2000-05-22
影响因子：
4.4
通讯作者：
Tidor, B
中科院分区：
文献类型：
--
作者：
Kangas, E;Tidor, B
设计以高亲和力和特异性结合靶分子（或相关靶家族）的配体分子是分子生物物理研究的基本目标。虽然通常认为静电相互作用可有助于结合特异性，但尚不清楚导致紧密结合的相互作用是否也必然导致高度特异性结合。在这里，我们利用最近开发的电荷优化技术，探讨在静电相互作用的背景下的亲和力特异性关系。使用模型问题，我们发现，亲和力优化的静电相互作用不一定会产生特异性。此外，我们开发了几种严格的方法，表明如何最好地干扰亲和力优化的配体电荷分布，以增加特异性，最小的牺牲在亲和力的目标或目标集。我们提供了一个理论框架，用于提高对任何数量的已知受体和/或结合模式，以及对未知受体的特异性。(C)2000年美国物理学会。[S0021-9606（00）51520-7]。
Designing ligand molecules that bind with high affinity and specificity to a target molecule (or a family of related targets) is a fundamental goal of molecular biophysical research. While it is generally recognized that electrostatic interactions can contribute to binding specificity, it is unclear whether the inclusion of interactions that result in tight binding also necessarily leads to highly specific binding. Here we make use of recently developed charge-optimization techniques to explore the affinity-specificity relation in the context of electrostatic interactions. Using model problems we find that affinity-optimized electrostatic interactions do not necessarily create specificity. Furthermore, we develop several rigorous methods that indicate how best to perturb affinity-optimized ligand-charge distributions to increase specificity with minimal sacrifice in affinity for the target or target set. We provide a theoretical framework for improving specificity against any number of known receptors and/or binding modes as well as against uncharacterized receptors. (C) 2000 American Institute of Physics. [S0021-9606(00)51520-7].