Burley S K, Wang A H, Votano J R, Rich A
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139.
Biochemistry. 1987 Aug 11;26(16):5091-9. doi: 10.1021/bi00390a030.
Single-crystal X-ray diffraction was used to determine the three-dimensional structures of two antigelling oligopeptides, L-lysyl-L-phenylalanyl-L-phenylalanine and L-phenylalanylglycylglycyl-D-phenylalanine, and two antisickling peptide analogues, L-phenylalanine benzyl ester and N-phenylacetyl-L-phenylalanine. Although these bisphenyl compounds are chemically quite different from one another, they demonstrate unusual structural similarities: The molecules have compact conformations in which the two phenyl rings are positioned approximately 5 A apart with interplanar angles approaching 90 degrees, thereby making intramolecular edge-to-face interactions. In addition, the polar atoms, nitrogen and oxygen, are in close proximity without forming intramolecular hydrogen bonds. The relative spatial distribution of polar and nonpolar atoms renders the structures compact and amphipathic. The intramolecular edge-to-face interaction between two aromatic rings, which brings a hydrogen atom with relative positive charge near the pi-electron cloud with relative negative charge, is enthalpically favorable and maintains the molecules in a compact and amphipathic conformation. Nonbonded potential energy calculations were used to characterize the energetics of the aromatic-aromatic interaction, and they showed that the observed geometry is stabilized enthalpically by a favorable interaction on the order of -1 to -2 kcal/mol. Structural differences between the two antisickling and the two antigelling agents suggest that molecular volume limits red cell membrane passage. These data provide a molecular structural framework from which to design and synthesize amphipathic bisphenyl compounds that both bind to deoxy sickle cell hemoglobin and cross the erythrocyte membrane.
利用单晶X射线衍射确定了两种抗凝胶寡肽（L-赖氨酰-L-苯丙氨酰-L-苯丙氨酸和L-苯丙氨酰甘氨酰甘氨酰-D-苯丙氨酸）以及两种抗镰状化肽类似物（L-苯丙氨酸苄酯和N-苯乙酰-L-苯丙氨酸）的三维结构。尽管这些双苯基化合物在化学性质上彼此差异很大，但它们展现出不同寻常的结构相似性：分子具有紧密的构象，其中两个苯环相距约5埃，面间角接近90度，从而形成分子内的边对面相互作用。此外，极性原子氮和氧彼此靠近，但未形成分子内氢键。极性和非极性原子的相对空间分布使结构紧凑且具有两亲性。两个芳香环之间的分子内边对面相互作用，使带相对正电荷的氢原子靠近带相对负电荷的π电子云，在焓上是有利的，并使分子保持紧凑且两亲的构象。使用非键合势能计算来表征芳香-芳香相互作用的能量学，结果表明观察到的几何结构通过约-1至-2千卡/摩尔量级的有利相互作用在焓上得以稳定。两种抗镰状化剂和两种抗凝胶剂之间的结构差异表明分子体积限制了红细胞膜的通过。这些数据提供了一个分子结构框架，据此可设计和合成既能与脱氧镰状细胞血红蛋白结合又能穿过红细胞膜的两亲性双苯基化合物。
