How Does the Recently Discovered Peptide MIP Exhibit Much Higher Binding Affinity than an Anticancer Protein p53 for an Oncoprotein MDM2
How Does the Recently Discovered Peptide MIP Exhibit Much Higher Binding Affinity than an Anticancer Protein p53 for an Oncoprotein MDM2
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最近发现的肽 MIP 如何对癌蛋白 MDM2 表现出比抗癌蛋白 p53 更高的结合亲和力
DOI：
10.1021/acs.jcim.9b00226
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发表时间：
2019
影响因子：
5.6
通讯作者：
Kinoshita Masahiro
中科院分区：
文献类型：
--
作者：
Yamada Tatsuya;Hayashi Tomohiko;Hikiri Simon;Kobayashi Naohiro;Yanagawa Hiroshi;Ikeguchi Mitsunori;Katahira Masato;Nagata Takashi;Kinoshita Masahiro
一种肿瘤蛋白MDM2结合到肿瘤抑制蛋白p53 （p53NTD）的极端n端肽区并抑制其抗癌活性。我们最近发现了一种名为MIP的肽，它对MDM2的结合亲和力比p53NTD高得多。实验表明，MDM2-MIP的结合自由能（BFE）比MDM2-p53NTD低约−4 kcal/mol。在这里，我们发展了一种理论方法，成功地再现了这种数量上的差异，并阐明了其物理起源。它使我们能够将BFE分解为各种能量和熵分量，评估它们的相对大小，并识别驱动或反对结合的物理因素。它也应该适用于评估配体对特定受体的结合亲和力的差异，这是现代化学的核心问题。在MDM2的情况下，MIP的高亲和力归因于水在结合时的平移和构型熵的较大增益。这一结果有助于设计一种对MDM2具有更高亲和力的肽，作为一种可靠的抗癌药物。
An oncoprotein MDM2 binds to the extreme N-terminal peptide region of a tumor suppressor protein p53 (p53NTD) and inhibits its anticancer activity. We recently discovered a peptide named MIP which exhibits much higher binding affinity for MDM2 than p53NTD. Experiments showed that the binding free energy (BFE) of MDM2-MIP is lower than that of MDM2-p53NTD by approximately −4 kcal/mol. Here, we develop a theoretical method which is successful in reproducing this quantitative difference and elucidating its physical origins. It enables us to decompose the BFE into a variety of energetic and entropic components, evaluate their relative magnitudes, and identify the physical factors driving or opposing the binding. It should be applicable also to the assessment of differences among ligands in the binding affinity for a particular receptor, which is a central issue in modern chemistry. In the MDM2 case, the higher affinity of MIP is ascribed to a larger gain of translational, configurational entropy of water upon binding. This result is useful to the design of a peptide possessing even higher affinity for MDM2 as a reliable drug against a cancer.