Computer-aided design of beta-sheet peptides

The design of beta -sheet proteins is still a challenge in the field of de novo protein design. Here, we have tested the validity of automatic design methods to create and/or improve beta -sheet peptides and proteins. We chos e Betanova, a three-stranded beta -sheet peptide, as target system, and, as an automatic design tool, a protein design algorithm called PERLA (protein engineering rotamer library algorithm). PERLA was used to define both stab ilising and destabilising single- and multiple-residue mutations of Betanov a. Conformational analysis by NMR spectroscopy and far-UV circular dichrois m (CD) allowed us to evaluate population differences among the set of desig ned peptides. Some of the new mutants are approximately 1 kcal/mol more sta ble than the wild-type peptide. Comparison of the scale of predicted and ob served stabilities demonstrates that they are in good agreement for most pe ptides studied. Our results show that automatic design algorithms can be su ccessfully applied to the design of beta -sheet peptides. (C) 2001 Academic Press.