GENERATING MULTIPLE CONFORMATIONS OF FLEXIBLE PEPTIDES IN SOLUTION BASED ON NMR NUCLEAR OVERHAUSER EFFECT DATA - APPLICATION TO DESMOPRESSIN
GENERATING MULTIPLE CONFORMATIONS OF FLEXIBLE PEPTIDES IN SOLUTION BASED ON NMR NUCLEAR OVERHAUSER EFFECT DATA - APPLICATION TO DESMOPRESSIN
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DOI：
10.1021/ja00138a019
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发表时间：
1995-08-23
影响因子：
15
通讯作者：
SYKES, BD
中科院分区：
文献类型：
--
作者：
WANG, JJ;HODGES, RS;SYKES, BD
报道了一种从核磁共振数据计算多肽溶液构象的计算程序PEPFLEX-II。它结合了用于结构计算的约束模拟退火法、用于NOE反向计算的系综平均完全松弛矩阵法和迭代NOE约束修正过程，其目标是计算与实验数据一致的最大范围的多肽构象。当NOE违规时，通过系统地增加距离约束的上界来实现距离约束的修改。通过使用较宽松的距离约束，并在模拟退火法中使用相对较小的NOE“力常数”，该过程允许分子在更宽的构象空间内搜索。结果是计算的系综NOE与原始实验NOE数据的拟合程度得到了改进。用两个收敛准则检验NOE实验数据的最佳拟合度和构象空间的最大复盖率。将PEPFLEX-II程序应用于水溶液中的去氨加压素纳米肽，得到了几个明确的结构家族。这些结构满足“良好的核磁共振结构”的所有标准，并且它们的系综平均值比任何单个结构都更符合实验NOE数据。
A computational procedure, PEPFLEX-II, for calculating multiple peptide solution conformations from NMR data is reported. It combines restrained simulated annealing for structural calculations, an ensemble averaged full relaxation matrix approach for NOE back calculation, and an iterative NOE restraint modification procedure into a protocol whose goal is to calculate the maximum range of peptide conformations consistent with the experimental data. The distance restraint modification is achieved by systematically increasing the upper boundary of the distance restraints when NOE violations occur. By using looser distance restraints and using a relatively small NOE ''force constant'' in the simulated annealing, the procedure allows the molecule to search over a wider conformational space. The result is an improved fit of the calculated NOE's for the ensemble to the original experimental NOE data. Two convergence criteria are used to test whether both the best fit of the experimental NOE data and the maximum coverage of conformational space are achieved. The PEPFLEX-II procedure has been applied to the nanopeptide desmopressin in aqueous solution, for which several well-defined structural families were generated. The structures satisfy all the criteria for ''good NMR structures'', and their ensemble average fits the experimental NOE data better than any one individual structure.