Tertiary structure prediction of peptides by Monte Carlo simulated annealing and its experimental verification

用蒙特卡罗模拟退火方法预测了牛胰蛋白酶抑制剂（BPTI） 16-36残基对应的肽片段的三级结构。模拟从随机选择的初始构象开始，并且在不施加实验约束的情况下进行。在20次模拟试验中，有7种构象显示出片状结构——两股由一个弯连接——尽管这种片状结构不像在天然BPTI中观察到的那样刚性。这些构象大多是环状的，并表现出类似原生的右旋。然而，能量最低的构象并不完全类似于天然结构。这表明，如果从天然蛋白中分离出含有16-36残基的片段，天然BPTI的刚性β -片构象仅对应于能量函数的局部最小值。对BPTI（16-36）在二甲亚砜溶液中的二维核磁共振分析也否定了刚性-薄片构象的存在。对所有20种最终构象的统计分析表明，残基18-24的肽段倾向于从延伸的β链中延伸出来，而残基30-35的肽段倾向于从延伸的β链中延伸出来。残基25-29段不倾向于形成任何确定的结构。在原生BPTI中，前两个片段参与β -sheet，后一个片段参与β -sheet。在此基础上，提出了一种新的折叠方案。同样的算法成功预测了甲状旁腺激素片段（34个氨基酸）的α -螺旋结构。因此，应该强调的是，目前的方法能够预测肽的三级结构，仅依赖于它们的氨基酸序列数据作为输入。

A tertiary structure of the peptide fragment corresponding to residues 16-36 of bovine pancreatic trypsin inhibitor (BPTI) is predicted nsing Monte Carlo simulated annealing. The simulation starts with randomly chosen initial conformations and is performed without imposing experimental constraints. Out of 20 siumulation trials, seven conformations show a sheet-like structure-two strands connected by a turn-although this sheet-like structure is not as rigid as that observed in native BPTI.These conformations are mostly looped and exhibit a native-like right-handed twist. However, the lowest-energy conformation does not resemble exactly the native structure. This indicates that the rigid beta-sheet conformation of native BPTI merely corresponds to a local minimum of the energy function if the fragment with residues 16-36 is isolated from the native protein. Two-dimensional NMR analyzes of BPTI (16-36) in dimethylsulfoxide solution also denied the existence of rigid beta-sheet conformation with the proper hydrogen bonds. A statistical analysis of all 20 final conformations suggests that the tendency for the peptide segments to from extended beta-strands is strong for those with residues 18-24, and moderate for those with residues 30-35. The segment of residues 25-29 does not tend to form any definite structure. In native BPTI,the former segments are involved in the beta-sheet and the latter in the turn. Based on this analysis, a novel folding scenario is proposed.The same algorithm successfully predicted alpha-helical structure of parathynoid hormore fragment (34 amino acids). Therefore, it should be emphasized that the present method was capable of predicting tertiary structure of peptides depending only on their amino acid sequence data as inputs.