Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design

We study the dynamic propensity of the backbone hydrogen bonds of the protein MDM2 (the natural regulator of the tumor suppressor p53) in order to determine its binding properties. This approach is fostered by the observation that certain backbone hydrogen bonds at the p53-binding site exhibit a dynamical propensity in simulations that differs markedly form their state-value (that is, formed/not formed) in the PDB structure of the apo protein. To this end, we conduct a series of hydrogen bond propensity calculations in different contexts: 1) computational alanine-scanning studies of the MDM2-p53 interface; 2) the formation of the complex of MDM2 with the disruptive small molecule Nutlin-3a (dissecting the contribution of the different molecular fragments) and 3) the binding of a series of small molecules (drugs) with different affinities for MDM2. Thus, the relevance of the hydrogen bond propensity analysis for protein binding studies and as a useful tool to complement existing methods for drug design and optimization will be made evident.

本研究针对肿瘤抑制因子p53的天然调控蛋白MDM2的主链氢键（backbone hydrogen bonds）的动态倾向性展开分析，旨在明确其结合特性。该研究思路源于以下观测发现：p53结合位点处的部分主链氢键在模拟实验中展现出的动态倾向性，与其在脱辅基蛋白（apo protein）的PDB（Protein Data Bank）结构中的状态值（即氢键形成/未形成）存在显著差异。为此，我们在多种情境下开展了一系列氢键倾向性计算：1）MDM2-p53界面的计算丙氨酸扫描（computational alanine-scanning）研究；2）MDM2与干扰性小分子Nutlin-3a形成复合物的相关分析，以解析不同分子片段的贡献程度；3）一系列对MDM2具有不同结合亲和力的小分子（药物）与MDM2的结合过程研究。由此可见，氢键倾向性分析在蛋白质结合研究中的应用价值，以及其作为补充现有药物设计与优化方法的实用工具的重要性，将得到充分彰显。