Study of MDM2 Binding to p53-Analogues: Affinity, Helicity, and Applicability to Drug Design
Study of MDM2 Binding to p53-Analogues: Affinity, Helicity, and Applicability to Drug Design
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DOI：
10.1021/ci800352c
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发表时间：
2009-04-01
影响因子：
5.6
通讯作者：
Ben-Tal, Nir
中科院分区：
文献类型：
--
作者：
Kalid, Ori;Ben-Tal, Nir
MDM2 是 p53 肿瘤抑制蛋白的关键调节因子。在这里，我们使用隐式溶剂 MD 和 MM-GB/SA 计算研究 p53 N 末端片段的修饰对其与 MDM2 结合的影响。我们提供现有实验数据的解释并预测突变对结合的影响。值得注意的是 1) 我们分析了 Ser/Thr 残基上调节性磷酸化的影响，并表明有利的静电和去溶剂化惩罚之间的平衡决定了磷酸化的影响； 2）我们比较了p53丙氨酸突变体在溶液中的螺旋稳定性，并提出了涉及氢键和疏水性堆积的几个残基的螺旋稳定作用； 3) 我们获得了一组拟肽抑制剂的计算亲和力和实验亲和力之间的良好相关性，无论是单独使用还是与p53类似物组合，证明了其对药物设计的潜在适用性。从技术方面，详细讨论了协议优化和仿真工具的选择。据我们所知，这是第一个发布的利用隐式溶剂 MD 生成的构象系综进行 MM-GB/SA 计算的示例。我们的结果表明，这种经典显式溶剂 MM-GB/SA 的高效变体可用于研究蛋白质-蛋白质相互作用和拟肽药物的设计。
MDM2 is a key regulator of the p53 tumor-suppressor protein. Here we study the effect of modifications of a p53 N-terminal fragment on its binding to MDM2, using implicit-solvent MD and MM-GB/SA calculations. We provide interpretation of existing experimental data and predict the effect of mutations on binding. Notably 1) We analyze the effect of regulatory phosphorylations at Ser/Thr residues and suggest that a balance between favorable electrostatics and desolvation penalties determines the effect of phosphorylation; 2) We compare the helical stability in solution of p53 alanine mutants and propose a helix stabilizing role for several residues involved in hydrogen bonding and hydrophobic packing; 3) We obtain good correlations between calculated and experimental affinities for a set of peptidomimetic inhibitors, both alone and in combination with p53 analogues, demonstrating potential applicability to drug design. From the technical aspect, protocol optimization and selection of simulation tools are addressed in detail. To the best of our knowledge this is the first published example of MM-GB/SA calculations utilizing a conformational ensemble generated with implicit solvent MD. Our results suggest that this highly efficient variant of classical explicit-solvent MM-GB/SA may be used for studying protein-protein interactions and for the design of peptidomimetic drugs.