Chemistry Department, United States Naval Academy, 572 Holloway Road, Annapolis, Maryland 21402, USA.
J Phys Chem A. 2010 Jan 21;114(2):1123-33. doi: 10.1021/jp9094535.
The design of peptide mimetic compounds is greatly facilitated by the identification of functionalities that can act as peptide replacements. The fluoroalkene moiety has recently been employed for that purpose. The purpose of this work is to examine the conformational ramifications of replacing peptide bonds with fluoroalkene moieties, thus generating peptidomimetics. The alanine dipeptide analogue (ADA) was chosen as a model compound. Three peptidomimetic systems were investigated including one generated by replacement of both peptide bonds of ADA, designated as DFA, and those generated by the single replacement of the C-terminal peptide bond and N-terminal peptide bond, designated as CFA and NFA, respectively. Conformations for all three systems were generated by exhaustive Monte Carlo searching. Relative conformational energies were calculated at the MP2/aug-cc-pVTZ/MP2/aug-cc-pVDZ (for DFA), MP2/-aug-cc-pVTZ//MP2/6-311+G(d,p), B3LYP/6-31+G(d)//B3LYP/6-31+G(d), and MMFF levels of theory. Aqueous phase conformational preferences were determined through calculations making use of continuum hydration models. The results indicate that replacement of both peptide bonds of ADA generates a peptidomimetic with conformational preferences where extended conformations are favored and the conformational profile is relatively insensitive to the nature of the surrounding medium. This is in contrast to ADA where the conformational preferences depend highly on the surrounding medium and where folded conformations with intramolecular hydrogen bonds are important in the absence of an interacting solvent. CFA and NFA are found to exhibit conformational preferences that do in some ways more closely resemble those of the alanine dipeptide analogue. This is particularly true in the case of NFA where interactions between the NH and CF groups are reminiscent of the intramolecular hydrogen bonding possible in ADA.
通过确定可以作为肽替代物的功能，极大地促进了肽模拟化合物的设计。最近，氟烯部分被用于该目的。这项工作的目的是研究用氟烯部分替代肽键以产生肽模拟物的构象延伸。选择丙氨酸二肽类似物（ADA）作为模型化合物。研究了三种肽模拟系统，包括通过替换 ADA 的两个肽键生成的一个系统，称为 DFA，以及通过单替换 C 末端肽键和 N 末端肽键生成的两个系统，分别称为 CFA 和 NFA。通过穷举蒙特卡罗搜索生成所有三个系统的构象。在 MP2/aug-cc-pVTZ/MP2/aug-cc-pVDZ（用于 DFA）、MP2/-aug-cc-pVTZ//MP2/6-311+G(d,p)、B3LYP/6-31+G(d)//B3LYP/6-31+G(d)和 MMFF 理论水平上计算相对构象能。通过利用连续体水合模型进行计算，确定水相构象偏好。结果表明，ADA 的两个肽键的替换生成了一种具有扩展构象偏好的肽模拟物，构象特征对周围介质的性质相对不敏感。这与 ADA 形成对比，ADA 的构象偏好高度依赖于周围介质，并且在没有相互作用溶剂的情况下，具有分子内氢键的折叠构象很重要。CFA 和 NFA 被发现表现出的构象偏好，在某些方面更类似于丙氨酸二肽类似物的构象偏好。在 NFA 的情况下尤其如此，其中 NH 和 CF 基团之间的相互作用类似于 ADA 中可能存在的分子内氢键。
