Enantioselective Molecular Recognition between β-Sheets

Abstract

This communication asks whether homochiral or heterochiral interaction is preferred between enantiomeric beta-sheets and finds that homochiral pairing is strongly preferred. Interactions between beta-sheets occur widely among proteins through pairing of the hydrogen-bonding edges. Although the hydrogen-bonding edges of both l- and d-beta-sheets put forth the same pattern of hydrogen-bond donor and acceptor groups, the side chains point in opposite directions. Homochiral pairing of beta-sheets generates structures in which the pleats and side chains of adjacent beta-strands are parallel to each other, while heterochiral pairing of beta-sheets generates structures in which the pleats and side chains are antiparallel. To test which pairing is preferred, we have prepared and studied the interactions of beta-sheets 1a-d, which comprise all l-amino acids, and beta-sheets 2a-c, which comprise all d-amino acids. Previous studies in our laboratory have established that these compounds form well-defined dimers in organic solvents. In the current study, 1H NMR experiments establish that when the l-beta-sheets (1) are mixed with the enantiomeric d-beta-sheets (2), homochiral beta-sheet dimers predominate, and only small quantities of heterochiral beta-sheet dimers form. Ratios of homochiral and heterochiral dimers ranging from 95.8:4.2 to 98.5:1.5 are measured in CDCl3 at 253 K, which correspond to statistically corrected free-energy differences of 3.1-4.2 kcal/mol (0.6-0.8 kcal/mol per interacting residue). Possible explanations for the high enantioselectivity of molecular recognition between beta-sheets include favorable nonbonded contacts between the adjacent beta-strands of the homochiral beta-sheets and poor fit of the heterochiral beta-strands, which should twist in opposite directions.

Origin of life. Primordial genetics: Information transfer in a pre-RNA world based on self-replicating beta-sheet amyloid conformers

“…Amyloid is normally found as a homochiral structure; the high enantioselectivity has been explained on the basis of favorable nonbonded contacts between adjacent beta-strands of the homochiral beta-sheets as compared with the poor fit of heterochiral ones (Chung and Nowick 2004, Wadai et al 2005. In a prebiotic setting, it is thus likely that homochiral peptides were preferentially incorporated in amyloid.…”

Bindungsmechanismen in supramolekularen Komplexen

“…[503] Peptide in Form von b-Faltblättern (Schema S17) liegen nach Modelluntersuchungen, in allerdings apolaren Medien, weitgehend in der homochiralen Konformation vor, die Stapelwechselwirkungen zwischen den Aminosäureresten R erlaubt. [504] Heterochirale Anordnungen werden bei basischen Aminosäuren, z. B. bei Polylysin bevorzugt, [505] wie aufgrund der Abstoßung zwischen den ionischen Gruppen in einer homochiralen Form zu erwarten ist.…”

High-resolution structures of a heterochiral coiled coil

“…The thermodynamic stability of this heterochiral tetramer is comparable to that of the diastereomeric all-L-peptide tetramer. In contrast, a study by Chung and Nowick suggests that backbone H-bond-mediated interactions characteristic of antiparallel β-sheet secondary structure are much more favorable for homochiral relative to heterochiral strand pairings (18). However, Nilsson and co-workers report that Significance D polypeptides represent an attractive platform for biomedical applications because of their resistance to proteolytic degradation.…”