Shenderovich M D, Kasprzykowski F, Liwo A, Sekacis I, Saulitis J, Nikiforovich G V
Institute of Organic Synthesis, Latvian Academy of Sciences, Riga.
Int J Pept Protein Res. 1991 Dec;38(6):528-38. doi: 10.1111/j.1399-3011.1991.tb01536.x.
A combined 1H-NMR and molecular mechanics study of [Cpp1, Sar7]AVP was performed in order to select the most probable conformations in DMSO solutions. The NMR constraints obtained were employed in the selection of starting conformations of the cyclic moiety of the analog. In particular, the diminished accessibility of the Asn5 NH proton to solvent and the close contact between Cpp1 and Cys6 C alpha H protons suggests a beta-turn conformation at the Phe3-Gln4 residues. Energy minimization was carried out both in the ECEPP/2 (rigid-valence geometry) and in the AMBER (flexible-valence geometry) force fields. Comparison of the experimental and calculated values of NMR characteristics has revealed that conformations containing type I, II, and III beta-turns at the Phe3-Gln4 residues are in reasonable agreement with the experimental data, with a dynamic equilibrium between the beta I (beta III) and beta II type structures of the cyclic part being the most probable. All of these conformations prefer the negative chirality of the disulfide bridge (theta 3 approximately -90 degrees). Five representative conformations were chosen for the acyclic tail: one with a beta I, one with a beta II'-turn at the Sar7-Arg8 residues, two extended-type conformations, and a conformation with a gamma-turn at Sar7. Because only high-energy extended conformations were in agreement with NMR data, it was concluded that the acyclic tail has considerable conformational flexibility in solution. The conformations obtained are discussed in terms of the structure-function relationship of the neurohypophyseal hormone analogs.
为了确定[Cpp1, Sar7]AVP在二甲基亚砜（DMSO）溶液中最可能的构象，进行了一项结合1H-NMR和分子力学的研究。获得的NMR约束条件被用于选择该类似物环状部分起始构象。特别是，Asn5的NH质子与溶剂的可及性降低以及Cpp1与Cys6的CαH质子之间的紧密接触表明在Phe3-Gln4残基处存在β-转角构象。在ECEPP/2（刚性价几何）和AMBER（柔性价几何）力场中都进行了能量最小化。NMR特征的实验值与计算值的比较表明，在Phe3-Gln4残基处含有I型、II型和III型β-转角的构象与实验数据合理相符，环状部分的βI（βIII）型和βII型结构之间的动态平衡是最可能的。所有这些构象都倾向于二硫键的负手性（θ3约为-90度）。为无环尾部选择了五个代表性构象：一个具有βI，一个在Sar7-Arg8残基处具有βII'-转角，两个伸展型构象，以及一个在Sar7处具有γ-转角的构象。由于只有高能伸展构象与NMR数据相符，因此得出结论，无环尾部在溶液中具有相当大的构象灵活性。根据神经垂体激素类似物的结构-功能关系对获得的构象进行了讨论。
