Hempel J C, Fine R M, Hassan M, Ghoul W, Guaragna A, Koerber S C, Li Z, Hagler A T
Biosym Technologies, Inc., San Diego, CA 92121-2777, USA.
Biopolymers. 1995 Sep;36(3):283-301. doi: 10.1002/bip.360360304.
In order to investigate conformational preferences of the 21-residue peptide hormone endothelin-1 (ET-1), an extensive conformational search was carried out in vacuo using a combination of high temperature molecular dynamics/annealing and a Monte Carlo/minimization search in torsion angle space. Fully minimized conformations from the search were grouped into families using a clustering technique based on rms fitting over the Cartesian coordinates of the atoms of the peptide backbone of the ring region. A wide range of local energy mining were identified even though two disulfide bridges (Cys1-Cys15 and Cys3-Cys11) constrain the structure of the peptide. Low energy conformers of ET-1 as a nonionized species in vacuo are stabilized by intramolecular interaction of the ring region (residues 1-15) with the tail (residues 16-21). Strained conformations for individual residues are observed. Conformational similarity to protein loops is established by matching to protein crystal structures. In order to assess the influence of aqueous environment on conformational preference, the electrostatic contribution to the solvation energy was calculated for ET-1 as a fully ionized species (Asp8, Lys9, Glu10, Asp18, N- and C-terminus) using a continuum electrostatics model (DelPhi) for each of the conformers generated in vacuo, and the total solvation free energy was estimated by adding a hydrophobic contribution proportional to solvent accessible surface area. Solvation dramatically alters the relative energetics of ET-1 conformers from that calculated in vacuo. Conformers of ET-1 favored by the electrostatic solvation energy in water include conformers with helical secondary structure in the region of residues 9-15. Perhaps of most importance, it was demonstrated that the contribution to solvation by an individual charge depends not only on its solvent accessibility but on the proximity of other charges, i.e., it is a cooperative effect. This was shown by the calculation of electrostatic solvation energy as a function of conformation with individual charges systematically turned "on" and "off". The cooperative effect of multiple charges on solvation demonstrated in this manner calls into question models that relate solvation energy simply to solvent accessibility by atom or residue alone.
为了研究21个残基的肽激素内皮素-1（ET-1）的构象偏好，利用高温分子动力学/退火与扭转角空间中的蒙特卡罗/最小化搜索相结合的方法，在真空中进行了广泛的构象搜索。通过基于环区域肽主链原子笛卡尔坐标的均方根拟合的聚类技术，将搜索得到的完全最小化构象分组为家族。尽管两个二硫键（Cys1-Cys15和Cys3-Cys11）限制了肽的结构，但仍发现了广泛的局部能量挖掘。ET-1在真空中作为非离子化物种的低能量构象异构体通过环区域（残基1-15）与尾部（残基16-21）的分子内相互作用而稳定。观察到个别残基的应变构象。通过与蛋白质晶体结构匹配，建立了与蛋白质环的构象相似性。为了评估水环境对构象偏好的影响，使用连续静电模型（DelPhi）对真空中生成的每个构象异构体，计算了ET-1作为完全离子化物种（Asp8、Lys9、Glu10、Asp18、N-和C-末端）时溶剂化能的静电贡献，并通过添加与溶剂可及表面积成比例的疏水贡献来估计总溶剂化自由能。溶剂化极大地改变了ET-1构象异构体相对于在真空中计算的相对能量学。水中静电溶剂化能青睐的ET-1构象异构体包括在残基9-15区域具有螺旋二级结构的构象异构体。也许最重要的是，研究表明，单个电荷对溶剂化的贡献不仅取决于其溶剂可及性，还取决于其他电荷之间的距离，即这是一种协同效应。通过系统地打开和关闭单个电荷，计算静电溶剂化能作为构象的函数，证明了这一点。以这种方式证明的多个电荷对溶剂化的协同效应，对仅将溶剂化能简单地与原子或残基的溶剂可及性相关联的模型提出了质疑。
