Liwo A, Tempczyk A, Ołdziej S, Shenderovich M D, Hruby V J, Talluri S, Ciarkowski J, Kasprzykowski F, Lankiewicz L, Grzonka Z
Department of Chemistry, University of Gdańsk, Poland.
Biopolymers. 1996 Feb;38(2):157-75. doi: 10.1002/(sici)1097-0282(199602)38:2<157::aid-bip3>3.0.co;2-u.
Conformational analysis of the neurohypophyseal hormones oxytocin (OT) and arginine-vasopressin (AVP) has been carried out using two different computational approaches and three force fields, namely by the Electrostatically Driven Monte Carlo (EDMC) method, with the Empirical Conformational Energy Program for Peptides (ECEPP/3) force field or with the ECEPP/3 force field plus a hydration-shell model, and by simulated-annealing molecular dynamics with the Consistent Valence Force Field (CVFF). The low-energy conformations obtained for both hormones were classified using the minimal-tree clustering algorithm and characterized according to the locations of beta-turns in the cyclic moieties. Calculations with the CVFF force field located conformations with a beta-turn at residues 3 and 4 as the lowest energy ones both for OT and for AVP. In the ECEPP/3 force field the lowest energy conformation of OT contained a beta-turn at residues 2 and 3, conformations with this location of the turn being higher in energy for AVP. The latter difference can be attributed to the difference in the size of the side chain in position 3 of the sequences: the bulkier phenylalanine residue of AVP in combination with the bulky Tyr2 residue hinders the formation of a turn at residues 2 and 3. Conformations of OT and AVP with a turn at residues 3,4 were in the best agreement with the x-ray structures of deaminooxytocin and pressinoic acid (the cyclic moiety of vasopressin), respectively, and with the nmr-derived distance constraints. Generally, the low-energy conformations obtained with the hydration-shell model were in a better agreement with the experimental data than the conformations calculated in vacuo. It was found, however, that the obtained low-energy conformations do not satisfy all of the nmr-derived distance constraints and the nuclear Overhauser effect pattern observed in nmr studies can be fully explained only by assuming a dynamic equilibrium between conformations with beta-turns at residues 2,3, 3,4, and 4,5. The low-energy structures of OT with a beta-turn at residues 2,3 have the disulfide ring conformations close to the model proposed recently for a potent bicyclic antagonist of OT [M. D. Shenderovich et al. (1994) Polish Journal of Chemistry, Vol. 25, pp. 921-927], although the native hormone differs from the bicyclic analogue by the conformation of the C-terminal tripeptide. This finding confirms the hypothesis of different receptor-bound conformations of agonists and antagonists of OT.
已使用两种不同的计算方法和三种力场对神经垂体激素催产素（OT）和精氨酸加压素（AVP）进行了构象分析，具体方法如下：通过静电驱动蒙特卡罗（EDMC）方法，使用肽的经验构象能量程序（ECEPP/3）力场或ECEPP/3力场加一个水化壳模型；以及通过使用一致价键力场（CVFF）的模拟退火分子动力学方法。使用最小树聚类算法对两种激素获得的低能构象进行分类，并根据环状部分中β-转角的位置进行表征。使用CVFF力场进行的计算表明，对于OT和AVP，残基3和4处具有β-转角的构象是能量最低的构象。在ECEPP/3力场中，OT的最低能量构象在残基2和3处包含一个β-转角，而AVP中该转角位置的构象能量较高。后一种差异可归因于序列中位置3处侧链大小的差异：AVP中较大的苯丙氨酸残基与较大的Tyr2残基相结合，阻碍了残基2和3处转角的形成。残基3、4处有转角的OT和AVP构象分别与脱氨催产素和加压素酸（加压素的环状部分）的X射线结构以及与核磁共振衍生的距离限制最为吻合。一般来说，使用水化壳模型获得的低能构象比在真空中计算的构象与实验数据的吻合度更好。然而，发现获得的低能构象并不满足所有核磁共振衍生的距离限制，并且核磁共振研究中观察到的核Overhauser效应模式只有通过假设残基2、3、3、4和4、5处具有β-转角的构象之间存在动态平衡才能得到充分解释。残基2、3处有β-转角的OT的低能结构具有的二硫键环构象与最近为一种有效的OT双环拮抗剂提出的模型接近[M. D. 申德罗维奇等人（1994年）《波兰化学杂志》，第25卷，第921 - 927页]，尽管天然激素与双环类似物在C端三肽的构象上有所不同。这一发现证实了OT激动剂和拮抗剂与受体结合时具有不同构象的假设。
