Three-stranded mixed artificial β-sheets

This paper describes the design, synthesis, and structural evaluation of a pair of compounds, comprising molecular templates and attached peptide strands, that mimic a small three-stranded mixed beta-sheet (6a and b). Each of these artificial beta-sheets is composed of two different molecular templates and two dipeptide strands. One of the templates is based on a 5-amino-2-methoxybenzoic hydrazide group that mimics the hydrogen-bonding functionality of a peptide beta-strand and serves as the top strand. This template forms a pattern of hydrogen bonds similar to that of an antiparallel beta-sheet with the middle peptide strand. The middle peptide strand forms a pattern of hydrogen bonds similar to that of a parallel beta-sheet with the bottom peptide strand. The other template holds the three strands next to each other and is based upon a triurea. In one artificial beta-sheet (6a), both the upper and middle urea groups and the middle and lower urea groups are linked by dimethylene (CH2CH2) chains; in the other (6b), the upper and middle urea groups are linked by a dimethylene chain, while the middle and lower urea groups are linked by a trimethylene (CH2CH2CH2) chain. H-1 NMR chemical shift and NOE studies establish that both of these compounds fold to adopt a hydrogen-bonded beta-sheetlike structure in CDCl3 solution. Chemical shift studies establish that three-stranded mixed artificial beta-sheets 6 are more tightly folded than their smaller two-stranded homologues, artificial parallel beta-sheet 1 and artificial antiparallel beta-sheet 3, as well as their three-stranded homologues with truncated beta-strand mimics, artificial beta-sheets 5. These studies show that the folding of artificial beta-sheets 6 is cooperative, with the interactions between the upper and middle strands and between the middle and lower strands reinforcing each other. (C) 2002 Elsevier Science Ltd. All rights reserved.