Zhu Y, Chen C C, King J A, Evans L B
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge 02139.
Biochemistry. 1992 Nov 3;31(43):10591-601. doi: 10.1021/bi00158a023.
The native state of a protein molecule in aqueous solutions represents one of the lowest states of Gibbs energy [Anfinsen, C.B. (1973) Science 181, 223-230]. Much progress has been made about the rules of protein folding [King, J. (1989) Chem. Eng. News 67, 32-54] and the dominant forces in protein folding [Dill, K.A. (1990) Biochemistry 29, 7133-7155]. However, the quantitative contributions of different Gibbs energy terms to protein stability remains a controversial issue [Moult, J., & Unger, R. (1991) Biochemistry 30, 3816-3824]. A molecular thermodynamic model has been proposed for the Gibbs energy of folding a residue in aqueous homopolypeptides from a random-coiled state to either the alpha-helix state or the beta-sheet state [Chen, C.-C., Zhu, Y., King, J.A., & Evans, L.B. (1992) Biopolymers 32, 1375-1392]. In this work, we present a generalization of the molecular thermodynamic model for the Gibbs energy of folding natural and synthetic heteropolypeptides from random-coiled conformations into alpha-helical conformations. The generalized model incorporates the intrinsic folding potential due to residue-solvent interactions, the cooperative folding effect due to residue-residue interactions, and the location and length of alpha-helices. The utility of the model was demonstrated by examining the stability of alpha-helical conformations of a number of natural polypeptides including C-peptide (residues 1-13) and S-peptide (residues 1-20) of RNase A (bovine pancreatic ribonuclease A), the P alpha fragment in BPTI (bovine pancreatic trypsin inhibitor), and synthetic polypeptides (the copolymers of different amino acid residues) including alanine-based peptides (16 or 17 residues long) in water. The computed Gibbs energies correspond well with the experimental data on helicity. The results also accounted for the effects of amino acid substitution and temperature on the stability of alpha-helical conformations of the test polypeptides.
蛋白质分子在水溶液中的天然状态代表吉布斯自由能的最低状态之一[安芬森，C.B.（1973年）《科学》181卷，223 - 230页]。在蛋白质折叠规则[金，J.（1989年）《化学与工程新闻》67卷，32 - 54页]以及蛋白质折叠中的主导作用力[迪尔，K.A.（1990年）《生物化学》29卷，7133 - 7155页]方面已经取得了很大进展。然而，不同吉布斯自由能项对蛋白质稳定性的定量贡献仍然是一个有争议的问题[莫尔特，J.，& 昂格尔，R.（1991年）《生物化学》30卷，3816 - 3824页]。已经提出了一个分子热力学模型，用于描述水性均聚多肽中一个残基从无规卷曲状态折叠成α - 螺旋状态或β - 折叠状态时的吉布斯自由能[陈，C.-C.，朱，Y.，金，J.A.，& 埃文斯，L.B.（1992年）《生物聚合物》32卷，1375 - 1392页]。在这项工作中，我们对分子热力学模型进行了推广，用于描述天然和合成杂聚多肽从无规卷曲构象折叠成α - 螺旋构象时的吉布斯自由能。该广义模型纳入了由于残基 - 溶剂相互作用产生的内在折叠势能、由于残基 - 残基相互作用产生的协同折叠效应以及α - 螺旋的位置和长度。通过研究多种天然多肽（包括核糖核酸酶A（牛胰核糖核酸酶A）的C -肽（1 - 13位残基）和S -肽（1 - 20位残基）、牛胰蛋白酶抑制剂中的Pα片段）以及合成多肽（不同氨基酸残基的共聚物，包括水中16或17个残基长的丙氨酸基肽）的α - 螺旋构象的稳定性，证明了该模型的实用性。计算得到的吉布斯自由能与螺旋度的实验数据吻合良好。结果还解释了氨基酸取代和温度对测试多肽α - 螺旋构象稳定性的影响。
