Effect of Stereochemistry and Hydrophobicity on the Self-Assembly of Phe-Phe-Nucleoside Conjugates

Molecular self-assembly of the minimal diphenylalanine (Phe-Phe) peptide building block shows unique morphological organizations and potential utility in biochemistry and biomaterials applications. Furthermore, the molecular engineering of nucleoside-conjugated Phe-Phe scaffolds allows the formation of diverse architectures with tunable biophysical properties. While the self-assembly of homochiral L-dipeptides is well characterized, stereochemistry is known to determine the conformation, which also governs self-assembly through molecular packing effects. Here, the effect of stereochemistry and hydrophobicity on Phe-Phe nucleoside conjugates using all four diastereomers [(L)Phe-(L)Phe, (D)Phe-(D Phe, (L)Phe-(D)Phe, and (D)Phe-(L)Phe] of Phe-Phe conjugates is systematically studied. The homochiral peptides form well-defined nanorods while the heterochiral dipeptides do not form any regular structures. Since heterocyclic nucleobases can self-assemble through hydrogen-bonded complementary base-pairing, the self-assembly of chiral nucleoside-conjugated Phe-Phe peptides is examined. All conjugated Phe-Phe peptides form seamless spherical particles. The completely or partially deprotected peptides do not assemble to any defined nanostructures suggesting that self-assembly is governed by the precise hydrophobic/hydrophilic balance in the assembling units. Contact angle measurements of the diastereomeric peptides reveal a subtle difference in stereochemistry-dependent molecular hydrophobicity. Taken together, it is revealed that the combination of chirality together with hydrophobic/hydrophilic balance within the peptides dictates the self-assembly of Phe-Phe dipeptide nucleoside conjugates.

Automated summary

The effect of stereochemistry and hydrophobicity on self-assembly of Phe-Phe dipeptide nucleoside conjugates has been studied. It was found that homochiral dipeptides form nanorod structures while heterochiral dipeptides do not form regular structures. The self-assembly of chiral nucleoside-conjugated Phe-Phe peptides results in spherical particles.