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
-sheet (
6a and b). Each of these artificial
-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
-strand and serves as the top strand. This template forms a pattern of hydrogen bonds similar to that of an antiparallel
-sheet with the middle peptide strand. The middle peptide strand forms a pattern of hydrogen bonds similar to that of a parallel
-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
-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. 1H NMR chemical shift and NOE studies establish that both of these compounds fold to adopt a hydrogen-bonded
-sheetlike structure in CDCl3 solution. Chemical shift studies establish that three-stranded mixed artificial
-sheets
6 are more tightly folded than their smaller two-stranded homologues, artificial parallel
-sheet
1 and artificial antiparallel
-sheet
3, as well as their three-stranded homologues with truncated
-strand mimics, artificial
-sheets
5. These studies show that the folding of artificial
-sheets
6 is cooperative, with the interactions between the upper and middle strands and between the middle and lower strands reinforcing each other.