Folding of the twisted .beta.-sheet in bovine pancreatic trypsin inhibitor

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Abstract
The dominant role of local interactions has been demonstrated for the formation of the strongly twisted antiparallel .beta.-sheet structure consisting of residues 18-35 in bovine pancreatic trypsin inhibitor. Conformational energy minimization has indicated that this .beta.-sheet has a strong twist even in the absence of the rest of the protein molecule. The twist is maintained essentially unchanged when energy minimization is carried out by starting from the native conformation. By starting from a nontwisted .beta.-sheet conformation of residues 18-35, a strongly twisted structure (higher in energy than the native) is obtained. The high twist of the native-like .beta.-sheet is a consequence of its amino acid sequence, but it is enhanced strongly by interchain interactions that operate within the .beta.-sheet. The existence of the twisted .beta.-sheet structure does not require the presence of a disulfide bond between residue 14 and residue 38. It actually may facilitate the formation of this bond. Therefore, it is likely that the .beta.-sheet structure forms during an earlier stage of folding than the formation of this disulfide bond. This study provides an example of the manner in which conformational energy calculations can be used to provide information about the probable pathway of the folding of a protein.