Role of solution conformation and flexibility of short peptide ligands that bind to the p56lck SH2 domain
Role of solution conformation and flexibility of short peptide ligands that bind to the p56lck SH2 domain
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DOI：
10.1016/s0968-0896(02)00536-9
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发表时间：
2003-03-20
影响因子：
3.5
通讯作者：
Liskamp, RMJ
中科院分区：
文献类型：
--
作者：
Dekker, FJ;de Mol, NJ;Liskamp, RMJ
药物设计中的一般方法是使配体更刚性以避免在受体结合时构象熵（Δ S（conf））的损失。我们假设，在pYEEI肽配体与p56（lck）SH 2结构域的高亲和力结合中，DeltaS（conf）的这种损失可能由于四倍带负电荷的pYEEI肽在结合的延伸构象中的预组织而减少。利用表面等离子体共振（SPR）竞争实验对Ac-pYEEI-NH 2、Ac-pYAAI-NH 2和Ac-pYGGI-NH 2肽进行热力学分析，以测定不同温度下的亲和常数。为了研究溶液构象和柔性的影响，进行了计算构象分析，从中计算溶液中的低能构象，并估计S-conf。结果发现，特别是在溶液中的pYE部分计算的低能构象类似于在结合态。在计算的最低能量构象中，异亮氨酸在溶液中向pY芳环弯曲，这种构象的发生通过NMR实验证实。的EE-和AA-肽的S-conf的估计值是相似的，这表明没有占主导地位的作用，由于静电排斥的溶液构象的预组织。显然，热力学遵循相同的熵-焓补偿关系，这也被发现适用于与p60（src）家族SH 2结构域结合的其他肽和肽模拟物。药物设计的结果的影响进行了讨论。(C)2002爱思唯尔科技有限公司版权所有。
A general approach in drug design is making ligands more rigid in order to avoid loss in conformational entropy (DeltaS(conf)) upon receptor binding. We hypothesized that in the high affinity binding of pYEEI peptide ligands to the p56(lck) SH2 domain this loss in DeltaS(conf) might be diminished due to preorganization of the fourfold negatively charged pYEEI peptide in the bound, extended, conformation. A thermodynamic analysis was performed on the peptides Ac-pYEEI-NH2, Ac-pYAAI-NH2 and Ac-pYGGI-NH2 using surface plasmon resonance (SPR) competition experiments to assay affinity constants at different temperatures. To study the effect of solution conformation and flexibility a computational conformation analysis was performed from which low energy conformations in solution were calculated, and S-conf estimated. It was found that the calculated low energy conformations for especially the pYE moiety in solution resemble that in the bound state. In the calculated minimum energy conformation in solution isoleucine is bent towards the pY aromatic ring, the occurrence of such conformation is experimentally confirmed by NMR. The estimated values for S-conf of the EE- and AA-peptide were similar, suggesting no predominant role of preorganization of the solution conformation due to electrostatic repulsion. Apparently the thermodynamics obey the same entropy-enthalpy compensation relationship, which also was found to hold for other peptides and peptidomimetics binding to p60(src) family SH2 domains. The implications of the results for drug design are discussed. (C) 2002 Elsevier Science Ltd. All rights reserved.