PRO-D-NME-AMINO ACID AND D-PRO-NME-AMINO ACID - SIMPLE, EFFICIENT REVERSE-TURN CONSTRAINTS
PRO-D-NME-AMINO ACID AND D-PRO-NME-AMINO ACID - SIMPLE, EFFICIENT REVERSE-TURN CONSTRAINTS
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DOI：
10.1021/ja00127a004
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发表时间：
1995-06-07
影响因子：
15
通讯作者：
MARSHALL, GR
中科院分区：
文献类型：
--
作者：
CHALMERS, DK;MARSHALL, GR
设计模拟物，当掺入肽，限制它采取一个逆转目前是相当大的兴趣。已经提出了许多双环二肽替代物，其固定转角的残基i + 1和i + 2的四个骨架二面角中的两个。在本文中，我们报告的构象分析的四肽含有几个双环模拟物，序列中含有脯氨酸和其他N-甲基氨基酸的i + 1和i + 2的位置的转折，和控制肽序列使用Monte Carlo构象搜索，然后在水中的分子动力学模拟隐含的溶剂化模型。这些研究表明，序列D-Pro-N-甲基氨基酸（D-Pro-NMe-AA）和Pro-D-NMe-AA在稳定残基i + 1和i + 2之间的酰胺键的反式构象方面是有效的，并将四个骨架二面角中的三个限制为与满足几个反向转角标准的结构相关的二面角。在许多情况下，这些序列比更复杂的多环模拟物更有效。D-Pro-NMe-AA和Pro-D-MMe-AA与常规肽合成方法相容，并且应该提供通过组合文库和结构-活性研究探测用于反转识别的受体的简单方法。
The design of mimetics that, when incorporated into a peptide, constrain it to adopt a reverse turn is currently of considerable interest. Numerous bicyclic dipeptide surrogates have been suggested which fix two of the four backbone dihedral angles of residues i + 1 and i + 2 of the turn. In this paper, we report the conformational analysis of tetrapeptides containing several bicyclic mimetics, sequences containing proline and other N-methylamino acids in the i + 1 and i + 2 positions of the turn, and control peptide sequences using a Monte Carlo conformational search followed by molecular dynamics simulation in water as implicitly represented by a solvation model. These studies indicate that the sequences D-Pro-N-methylamino acid (D-Pro-NMe-AA) and Pro-D-NMe-AA are effective at stabilizing the trans conformer of the amide bond between residues i + 1 and i + 2 and constraining three of the four backbone dihedral angles to those associated with structures which satisfy several criteria for reverse turns. In many cases, these sequences were more effective than more complicated polycyclic mimetics. D-Pro-NMe-AA and Pro- D-MMe-AA are compatible with conventional peptide synthesis methods and should provide a simple method to probe receptors for reverse-turn recognition through combinatorial libraries and structure-activity studies.