The design of an inhibitor using alpha, beta-dehydro residues

X-ray crystallography and NMR spectroscopic studies on peptides containing alpha, beta-unsaturated (dehydro) residues have indicated that the steric effects caused by the dehydro residue are strong and predictable, and such residues can be used to generate specific peptide structures. In particular, dehydro-Alanine (delta Ala) is found to adopt an extended conformation and also induces a definite conformation in the neighboring saturated residue. In order to design a sequence that would fold into a known three-dimensional structure, we have undertaken a systematic theoretical study of the preferred conformations of tetrapeptide sequences of the type N-Ac-delta Ala-X-delta Ala-NHCH3 (x = Gly, L-Ala, L-Val, L-Leu, L-Lys, L-Arg, L-Phe). The methodology and parameters used have been standardized against sequences with known crystal structures. In all the sequences a consistent folding pattern is observed in which the delta Ala residues are in an extended conformation with phi approximately 140 degrees and psi approximately -40 degrees. The results are used to predict a sequence which has a structure very similar to that of the binding loop region of the bovine pancreatic trypsin inhibitor (BPTI).