Modeling of peptides containing D-amino acids: implications on cyclization

Abstract

Cyclic peptides are therapeutically attractive due to their high bioavailability, potential selectivity, and scaffold novelty. Furthermore, the presence of D-residues induces conformational preferences not followed by peptides consisting of naturally abundant L-residues. Therefore, comprehending how amino acids induce turns in peptides, subsequently facilitating cyclization, is significant in peptide design. Here, we performed 20-ns explicit-solvent molecular dynamics simulations for three diastereomeric peptides with stereochemistries: LLLLL, LLLDL, and LDLDL. Experimentally LLLLL and LDLDL readily cyclize, whereas LLLDL cyclizes in low yield. Simulations at 310 K produced conformations with inter-terminal hydrogen bonds that correlated qualitatively with the experimental cyclization trend. Energies obtained for representative structures from quantum chemical (B3LYP/PCM/cc-pVTZ//HF/6-31G*) calculations predicted pseudo-cyclic and extended conformations as the most stable for LLLLL and LLLDL, respectively, in agreement with the experimental data. In contrast, the most stable conformer predicted for peptide LDLDL was not a pseudo-cyclic structure. Moreover, D-residues preferred the experimentally less populated alpha(L) rotamers even when simulations were performed at a higher temperature and with strategically selected starting conformations. Energies calculated with molecular mechanics were consistent only with peptide LLLLL. Thus, the conformational preferences obtained for the all L: -amino acid peptide were in agreement with the experimental observations. Moreover, refinement of the force field is expected to provide far-reaching conformational sampling of peptides containing D-residues to further develop force field-based conformational-searching methods.

Synthesis of Cyclic Peptides through Direct Aminolysis of Peptide Thioesters Catalyzed by Imidazole in Aqueous Organic Solutions

“…Molecular dynamics simulations and quantum mechanics calculations were also applied to these three peptide thioesters. 18 The results are consistent with the cyclization tendencies.…”

Design and synthesis of Hsp90 inhibitors: Exploring the SAR of Sansalvamide A derivatives

“…This work has demonstrated that 3 compounds containing these motifs were significantly more potent than the natural product peptide, San A-amide 6. Our work has been validated by several current examples in the recent literature where cyclic peptides, and specifically pentapeptides, with both an N-methyl and D-amino acid lock the macrocycle into a single conformation 14–16. Data from these studies suggest that the compounds, once locked into a major conformation, will be appropriately positioned as a beta or gamma turn, which is likely to lead to a well-defined, high affinity interaction with the protein target 17, 18…”

Contemporary strategies for peptide macrocyclization

“…Peptides consisting only of l-residues, devoid of other turn-inducing structures, will often not cyclize until the C-terminal α-carbon has epimerized to the d-configuration 35 . The effect of d-amino acids on peptide macrocyclization have also been modelled theoretically 36 .…”