Conformational Determinants of the Activity of Antiproliferative Factor Glycopeptide
Conformational Determinants of the Activity of Antiproliferative Factor Glycopeptide
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DOI：
10.1021/ci400147s1
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发表时间：
2013-05-01
影响因子：
5.6
通讯作者：
MacKerell, Alexander D.
中科院分区：
文献类型：
--
作者：
Mallajosyula, Sairam S.;Adams, Kristie M.;MacKerell, Alexander D.
间质性膀胱炎中涉及的抗增殖因子（APF）是一种糖基化九肽（TVPAAVVVA），含有与N-末端苏氨酸连接的唾液酸化核心1 α-O-二糖。APF的化学结构用光谱技术推断，并通过全合成确认。合成的APF提供了一个平台，研究氨基酸修饰及其对APF活性的影响，基于此，以前提出了APF活性的构效关系（SAR）。然而，该SAR模型不能解释与肽序列中的微小改变相关的活性变化。提出的是14 APF衍生物的计算分析，以确定结构的趋势，从中获得更详细的SAR。发现APF活性由碳水化合物-肽和肽-肽相互作用之间的密切相互作用决定。前者涉及氢键和疏水相互作用，后者主要是疏水相互作用。高度柔性的疏水肽采用由低能垒分离的塌陷构象。APF活性与氨基酸4A、6V和8V相关的疏水性聚集相关。肽构象对单点突变高度敏感，这解释了实验趋势。所提出的SAR将作为潜在治疗效用的更有效的APF类似物的铅优化的指导。
The antiproliferative factor (APF) involved in interstitial cystitis is a glycosylated nonapeptide (TVPAAVVVA) containing a sialylated core 1 alpha-O-disaccharide linked to the N-terminal threonine. The chemical structure of APF was deduced using spectroscopic techniques and confirmed using total synthesis. The synthetic APF provided a platform to study amino acid modifications and their effect on APF activity, based on which a structure-activity relationship (SAR) for APF activity was previously proposed. However, this SAR model could not explain the change in activity associated with minor alterations in the peptide sequence. Presented is computational analysis of 14 APF derivatives to identify structural trends from which a more detailed SAR is obtained. The APF activity is found to be dictated by the close interplay between carbohydrate-peptide and peptide-peptide interactions. The former involves hydrogen bond and hydrophobic interactions, and the latter is dominated by hydrophobic interactions. The highly flexible hydrophobic peptide adopts collapsed conformations separated by low energy barriers. APF activity correlates with hydrophobic clustering associated with amino acids 4A, 6V, and 8V. Peptide conformations are highly sensitive to single point mutations, which explain the experimental trends. The presented SAR will act as a guide for lead optimization of more potent APF analogues of potential therapeutic utility.