biostudies-literatureUnknown13(26)Li XNational Institutes of HealthIn 1953, Pauling and Corey postulated "rippled" β-sheets, composed of a mixture of d- and l-peptide strands, as a hypothetical alternative to the now well-established structures of "pleated" β-sheets, which they proposed as a component of all-l-proteins. Growing interest in rippled β-sheets over the past decade has led to the development of mixtures of d- and l-peptides for biomedical applications, and a theory has emerged that mixtures of enantiomeric β-sheet peptides prefer to co-assemble in a heterochiral fashion to form rippled β-sheets. Intrigued by conflicting reports that enantiomeric β-sheet peptides prefer to self-assemble in a homochiral fashion to form pleated β-sheets, we set out address this controversy using two β-sheet peptides derived from Aβ_17-23 and Aβ_30-36, peptides 1a and 1b. Each of these peptides self-assembles to form tetramers comprising sandwiches of β-sheet dimers in aqueous solution. Through solution-phase NMR spectroscopy, we characterize the different species formed when peptides 1a and 1b are mixed with their respective d-enantiomers, peptides <i>ent</i>-1a and <i>ent</i>-1b. ¹H NMR, DOSY, and ¹H,¹⁵N-HSQC experiments reveal that mixing peptides 1a and <i>ent</i>-1a results in the predominant formation of homochiral tetramers, with a smaller fraction of a new heterochiral tetramer, and mixing peptides 1b and <i>ent</i>-1b does not result in any detectable heterochiral assembly. ¹⁵N-edited NOESY reveals that the heterochiral tetramer formed by peptides 1a and <i>ent</i>-1a is composed of two homochiral dimers. Collectively, these NMR studies of Aβ-derived peptides provide compelling evidence that enantiomeric β-sheet peptides prefer to self-assemble in a homochiral fashion in aqueous solution.Chemical science7739-7746https://www.ebi.ac.uk/biostudies/studies/S-EPMC9258340biostudies-literatureEnantiomeric β-sheet peptides from Aβ form homochiral pleated β-sheets rather than heterochiral rippled β-sheets.PMC9258340Li XRios SENowick JSfalseEnantiomeric β-sheet peptides from Aβ form homochiral pleated β-sheets rather than heterochiral rippled β-sheets.In 1953, Pauling and Corey postulated "rippled" β-sheets, composed of a mixture of d- and l-peptide strands, as a hypothetical alternative to the now well-established structures of "pleated" β-sheets, which they proposed as a component of all-l-proteins. Growing interest in rippled β-sheets over the past decade has led to the development of mixtures of d- and l-peptides for biomedical applications, and a theory has emerged that mixtures of enantiomeric β-sheet peptides prefer to co-assemble in a heterochiral fashion to form rippled β-sheets. Intrigued by conflicting reports that enantiomeric β-sheet peptides prefer to self-assemble in a homochiral fashion to form pleated β-sheets, we set out address this controversy using two β-sheet peptides derived from Aβ_17-23 and Aβ_30-36, peptides 1a and 1b. Each of these peptides self-assembles to form tetramers comprising sandwiches of β-sheet dimers in aqueous solution. Through solution-phase NMR spectroscopy, we characterize the different species formed when peptides 1a and 1b are mixed with their respective d-enantiomers, peptides <i>ent</i>-1a and <i>ent</i>-1b. ¹H NMR, DOSY, and ¹H,¹⁵N-HSQC experiments reveal that mixing peptides 1a and <i>ent</i>-1a results in the predominant formation of homochiral tetramers, with a smaller fraction of a new heterochiral tetramer, and mixing peptides 1b and <i>ent</i>-1b does not result in any detectable heterochiral assembly. ¹⁵N-edited NOESY reveals that the heterochiral tetramer formed by peptides 1a and <i>ent</i>-1a is composed of two homochiral dimers. Collectively, these NMR studies of Aβ-derived peptides provide compelling evidence that enantiomeric β-sheet peptides prefer to self-assemble in a homochiral fashion in aqueous solution.2022-01-01T00:00:00Z2022 Jul2025-04-05T14:26:09.741Z2025-04-05T14:26:09.741ZS-EPMC92583403586590110.1039/d2sc02080g