Therapeutic Peptide Modelling

Keywords: Cancer, QM/MM, NOESY, Gaussian 09, AMBER

Peptides present themselves as promising drug candidates, but the body’s natural proteolytic degradation pathways have hindered their application. Peptide design, however, can benefit significantly from the synthetic incorporation of non-standard amino acids such as β-amino acids, D-amino acids, and α,β-dehydroamino acids (ΔAAs), which are resistant to proteolysis. The literature is replete with a diversity of ‘designer residues’ used to fine-tune backbone conformations, side-chain functionality, and reactivity. One type of residue that merits further exploration is dehydroamino acids. Dehydroamino acid-containing peptides exhibit potent natural antibiotic, antifungal, antitumor, and phytotoxic bioactivity.

For example, Yaku’amide A is an extremely rare peptide isolated from the deep-sea sponge Ceratopsion sp. Identification and characterization of this peptide unveiled its curious structural profile and several dehydroamino acids. When tested against an array of 39 human cancer cell lines, YA exhibited cytotoxicity against P388 murine leukemia cells via a potentially novel mode of action. Unfortunately, many medically relevant peptides, such as Yaku’amide, often contain non-standard amino acids and require parameterization for computational studies. One approach to handling complex peptides lacking robust parameters is quantum mechanics (QM)/molecular mechanic (MM) hybrid simulations that rely on forcefields and ab initio calculations to balance the cost-accuracy tradeoff.

Related Publications:

Lo, C.L.; Joaquin, D.L.; Moya, D.A.; Ramos, A.R.; Kastner, D.W.; White, S.M.; Christensen, B.L.; Naglich, J.G.; Degnen, W.J.; Castle, S.L.; “Synthesis and evaluation of potent yaku’amide analogs.” Chemical Science, 13(7), 1899-1905 2022.

Joaquin, D.; Lee, M.; Kastner, D.W.; Singh, J.; Shardon, D.; Damstedt, G.; Castle, S.L.; “Impact of Dehydroamino Acids on the Structure and Stability of Incipient 310-Helical Peptides” The Journal of Organic Chemistry, 3(85), 1601-1613 2020.

Jalan, A.; Kastner, D.W.; Webber, K.G.I.; Smith, M.; Price, J.L.; Castle, S.L.; “Bulky Dehydroamino Acids Enhance Proteolytic Stability and Folding in β-Hairpin Peptides.” Organic Letters, 19(19), 5190-5193 2018.

Kastner, D.W.; Castle, S.L.; “ONIOM(DFT:MM) Study of Yaku’amide A and Analogues.” Journal of Undergraduate Research, ORCA Grant 2018.

Kastner, D.W.; Ankur, J.; Castle, S.L.; “Progress Toward Synthetically Simplified Natural Anticancer Peptide.” ScholarsArchive, 2572-4479 2018.

Kastner, D.W.; Ankur, J.; Castle, S.L.; “Computational Predictions of β-Hairpins Containing Bulky Dehydroamino Acids.” ScholarsArchive, 2572-4479 2017.