Kim A, Szoka F C
Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143-0446.
Pharm Res. 1992 Apr;9(4):504-14. doi: 10.1023/a:1015892313856.
The location of amino acids in soluble or membrane proteins is related to the hydrophobicity of the side chains. Amino acid hydrophobicity values are based upon the thermodynamics of transfer from an aqueous to a nonaqueous environment. However, for certain hydrophilic residues uncertainty exists on the appropriate hydrophobicity values. We have measured the octanol-water partition coefficients (Po/w) of tripeptides of the sequence N-14C-acetyl-Ala-X-Ala-NH-tButyl (AcAlaXAlaNHtButyl), where the central residue X was either Gly, Ala, Phe, Trp, Pro, His, Asp, or Glu. The Po/w for the tripeptides agreed reasonably well with values calculated by the fragment method of D. J. Abraham and A. J. Leo (Proteins Struct. Func. Gen. 2, 130-152, 1987). The log Po/w of the uncharged form was 1.6, 2.7, and 2.5 greater than the log Po/w of the ionized form for the His, Asp, and Glu peptide, respectively. The new data on the pH dependence of the ionizable side chains, His, Asp, and Glu, should result in better prediction of the partition coefficient of peptides as a function of pH. The thermodynamic parameters were determined from the temperature dependence of partitioning. In the temperature range studied (2 to 65 degrees C) the transfer of tripeptides from water to octanol was entropy governed except for the ionized peptides. A heat capacity term was necessary to account for the transfer of tripeptides containing non polar residues. The heat capacity change for transfer from water into octanol was -45, -73, -81, and -88 cal/mol K for Ala, Phe, Trp, and Pro peptides, respectively. Peptides containing Gly, His (pH 7.2), and the uncharged forms of Asp, Glu, and His did not show a significant change in heat capacity. The side-chain contribution of the central residue X (delta Gx) to the free energy of transfer was obtained from the difference between the free energy of transfer of the peptide containing the central residue X and the Gly peptide; delta Gx = delta G(AcAlaXAlaNHtButyl) - delta G(AcAlaGlyAlaNHtButyl). The relative order of hydrophobicity of the side chains correlated well with previous studies. However, a significant difference was found for the absolute hydrophobicity between the present study and experimental data on N-acetyl amino acid amide derivatives (J. Fauchere and V. Pliska, Eur. J. Med. Chem. 18(4), 369-375, 1983).(ABSTRACT TRUNCATED AT 400 WORDS)
氨基酸在可溶性或膜蛋白中的位置与侧链的疏水性有关。氨基酸疏水性值基于从水性环境转移到非水性环境的热力学。然而，对于某些亲水性残基，合适的疏水性值存在不确定性。我们测量了序列为N-14C-乙酰基-Ala-X-Ala-NH-叔丁基（AcAlaXAlaNHtButyl）的三肽的正辛醇-水分配系数（Po/w），其中中心残基X为Gly、Ala、Phe、Trp、Pro、His、Asp或Glu。这些三肽的Po/w与D. J. 亚伯拉罕和A. J. 利奥的片段法计算值（《蛋白质结构、功能与遗传学》2，130 - 152，1987）相当吻合。对于His、Asp和Glu肽，不带电形式的log Po/w分别比离子化形式的log Po/w大1.6、2.7和2.5。关于可电离侧链His、Asp和Glu的pH依赖性的新数据，应能更好地预测肽的分配系数随pH的变化。通过分配的温度依赖性确定了热力学参数。在所研究的温度范围（2至65摄氏度）内，除了离子化肽外，三肽从水转移到正辛醇是由熵控制的。需要一个热容项来解释含有非极性残基的三肽的转移。从水转移到正辛醇时，Ala、Phe、Trp和Pro肽的热容变化分别为-45、-73、-81和-88 cal/mol K。含有Gly、His（pH 7.2）以及Asp、Glu和His的不带电形式的肽，其热容没有显著变化。中心残基X（ΔGx）对转移自由能的侧链贡献是通过含有中心残基X的肽与Gly肽的转移自由能之差获得的；ΔGx = ΔG(AcAlaXAlaNHtButyl) - ΔG(AcAlaGlyAlaNHtButyl)。侧链疏水性的相对顺序与先前的研究结果很好地相关。然而，在本研究与N-乙酰基氨基酸酰胺衍生物的实验数据（J. 福歇尔和V. 普利什卡，《欧洲药物化学杂志》18(4)，369 - 375，1983）之间，发现绝对疏水性存在显著差异。（摘要截取自400字）
