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

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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.