Michel A G, Lajoie G, Hassani C A
Laboratory of Structural Chemistry and Molecular Modelling, University of Sherbrooke, Quebec, Canada.
Int J Pept Protein Res. 1990 Dec;36(6):489-98. doi: 10.1111/j.1399-3011.1990.tb00987.x.
The crystal structures of HCO-Met-Leu-Phe-OC(CH3)3, (CH25H39N3O5S), fMLP-OtBu, and HCO-Met psi [CSNH]-Leu-Phe-OCH3, (C22H33N3O4S2), fMS LP-OMe, have been determined by single crystal X-ray diffraction, and their conformational properties investigated by molecular mechanics energy calculations. Crystals of fMLP-OtBu are monoclinic, space group P2(1), a = 12.027(4), b = 9.492(3), c = 12.660(4) A, beta = 101.99(3) degrees, Z = 2; those of fMS LP-OMe are orthorhombic, space group P2(1)2(1)2(1), a = 7.130(1), b = 12.097(2), c = 31.060(5) A, Z = 4. The first compounds fMLP-OtBu is the t-butyl ester of the tripeptide fMLP that represents one of the most potent compounds in inducing the lysozyme release from human neutrophils that reflects the chemotactic activity. From the crystal structure, it is shown that the orientation of the phenylalanine side chain is largely affected by the presence of the bulky group. fMSLP-OMe was shown to be inactive after thionation of the methionine residue in the original tripeptide. Nevertheless, the crystal structure does not reveal any influence of the presence of the thionated peptidic bond on the backbone conformation. The X-ray results have been used to generate parameters for empirical energy calculations. Subsequently, a strategy based on random generation of conformations followed by energy-minimization was applied to investigate the conformational space of thiopeptides, in comparison with normal peptides. From molecular free energy calculations, it is shown that the main influence of the introduction of a thioamide bond on the molecular structure is to prevent the existence of C7(eq) conformations involving the thiomethionine residue. Consequently, a larger number of conformers are found to form intramolecular hydrogen bonds involving the formyl group, reducing its availability to interact with the receptor. For the first time, the theoretical prediction of the existence of C7eq conformations for fMLP is made. The resulting conformers are compared to previously active structures of these chemotactic agents.
已通过单晶X射线衍射确定了HCO-Met-Leu-Phe-OC(CH3)3（(CH25H39N3O5S）、fMLP-OtBu以及HCO-Met psi [CSNH]-Leu-Phe-OCH3（C22H33N3O4S2）、fMS LP-OMe的晶体结构，并通过分子力学能量计算研究了它们的构象性质。fMLP-OtBu的晶体为单斜晶系，空间群P2(1)，a = 12.027(4)，b = 9.492(3)，c = 12.660(4) Å，β = 101.99(3)°，Z = 2；fMS LP-OMe的晶体为正交晶系，空间群P2(1)2(1)2(1)，a = 7.130(1)，b = 12.097(2)，c = 31.060(5) Å，Z = 4。第一种化合物fMLP-OtBu是三肽fMLP的叔丁酯，它是诱导人中性粒细胞释放溶菌酶的最有效化合物之一，反映了趋化活性。从晶体结构可知，苯丙氨酸侧链的取向在很大程度上受庞大基团存在的影响。fMSLP-OMe在原三肽中甲硫氨酸残基硫代化后显示无活性。然而，晶体结构并未揭示硫代肽键的存在对主链构象有任何影响。X射线结果已用于生成经验能量计算的参数。随后，应用一种基于随机生成构象然后进行能量最小化的策略来研究硫肽的构象空间，并与正常肽进行比较。从分子自由能计算可知，引入硫酰胺键对分子结构的主要影响是阻止涉及硫代甲硫氨酸残基的C7(eq)构象的存在。因此，发现大量构象体形成涉及甲酰基的分子内氢键，降低了其与受体相互作用的可用性。首次对fMLP的C7eq构象的存在进行了理论预测。将所得构象体与这些趋化剂先前的活性结构进行了比较。
