Computational Insight into the Intercalating Properties of Cryptolepine

Journal article

Ferguson, G., Slocombe, L., Lisgarten, J., Lisgarten, D., Wright, C., Talbert, R., Palmer, R., Howlin, B. and Sacchi, M. 2025. Computational Insight into the Intercalating Properties of Cryptolepine. ACS Omega. 10 (18), pp. 18283-18290. https://doi.org/10.1021/acsomega.4c08666
AuthorsFerguson, G., Slocombe, L., Lisgarten, J., Lisgarten, D., Wright, C., Talbert, R., Palmer, R., Howlin, B. and Sacchi, M.
AbstractDNA is held together by hydrogen bonding between nucleobases (adenine-thymine, guanine-cytosine) and van der Waals interactions between adjacent base pairs’ π orbitals. Intercalating molecules with quasiplanar structures utilize van der Waals interactions to bind between DNA base pairs. Experimental studies have shown that Cryptolepine preferentially intercalates between nonalternating cytosine and guanine base pairs. However, an atomic-scale mechanism that can explain the selective intercalation is still missing. Using molecular dynamics and density functional theory, we demonstrate how Cryptolepine binds to DNA base pairs, rationalizing its selectivity by analyzing the intermolecular bonding strength predicted by Umbrella Sampling and Free Energy Perturbation calculations. Cryptolepine is stable in all DNA base conformations studied, and the binding is a combination of van der Waals interactions with the nucleobases surrounding its π system and hydrogen bonds with the DNA backbone and nucleobases. Our model predicts a preference for cytosine and guanine base pairs with a more prominent preference for alternating cytosine and guanine base pairs. These findings illustrate Cryptolepine’s binding mechanism to DNA and highlight the importance of hydrogen bonds and van der Waals interactions.
KeywordsBinding energy; Chemical calculations; Chemical structure; Genetics; Noncovalent interactions
Year2025
JournalACS Omega
Journal citation10 (18), pp. 18283-18290
PublisherAmerican Chemical Society
ISSN2470-1343
Digital Object Identifier (DOI)https://doi.org/10.1021/acsomega.4c08666
Official URLhttps://\https://pubs.acs.org/doi/10.1021/acsomega.4c08666
FunderJohn Templeton Foundation
Leverhulme Trust
Royal Society
Publication dates
Online28 Apr 2025
Publication process dates
Accepted16 Apr 2025
Deposited15 May 2025
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Open
Output statusPublished
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