Molecular Dynamics Insights into Peptide-Based Tetrodotoxin Delivery Nanostructures
Tetrodotoxin (TTX), a potent Site-1 sodium channel blocker (S1SCB), offers highly effective local anesthetic properties with minimal addiction potential. To fully leverage TTX’s capabilities as a local anesthetic, it is crucial to develop a drug delivery system that balances its systemic toxicity wi...
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2024-12-01
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| author | Shenghan Song Xinyu Xia Temair Shorty Tongtong Li Amy O. Stevens Chao Zhao Yi He |
| author_facet | Shenghan Song Xinyu Xia Temair Shorty Tongtong Li Amy O. Stevens Chao Zhao Yi He |
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| description | Tetrodotoxin (TTX), a potent Site-1 sodium channel blocker (S1SCB), offers highly effective local anesthetic properties with minimal addiction potential. To fully leverage TTX’s capabilities as a local anesthetic, it is crucial to develop a drug delivery system that balances its systemic toxicity with its therapeutic efficacy. Recent studies have shown that peptide mixtures, derived from fragments of Site-1 sodium channel proteins and enhanced with hydrophobic tails (designated MP1 and MP2), can self-assemble into nanostructures that exhibit remarkable sustained-release capabilities for TTX. Despite the profound impact that the addition of a hydrophobic tail has on altering the release behavior of the original peptides, the atomic-level interactions and mechanisms underlying this phenomenon remain poorly understood. In this study, a combination of ColabFold and molecular dynamics (MD) simulations were used to investigate the binding interactions between TTX and the nanostructures formed by MP1 and MP2 at an atomic level. Our findings agree with experimental observations and indicate that the MP1/MP2 nanostructure demonstrates greater stability and higher binding affinity for TTX compared to their non-modified counterparts, P1 and P2. The analysis of the simulations revealed that charged amino acids, specifically aspartic acid (ASP) and glutamic acid (GLU), on the peptides are crucial for strong TTX binding and serve as the primary functional sites. Additionally, the stability of the nanostructure significantly affects TTX binding affinity, elucidating why P1, P2, MP1, and MP2 exhibit different binding capabilities despite containing identical charged residues. The results reported here may provide fundamental information to drive future research and enhance the development of TTX-based drug delivery systems. |
| format | Article |
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| institution | Kabale University |
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| spelling | doaj-art-4a59857b7a8f482998568808382c6cb92025-01-10T13:18:45ZengMDPI AGMolecules1420-30492024-12-013016110.3390/molecules30010061Molecular Dynamics Insights into Peptide-Based Tetrodotoxin Delivery NanostructuresShenghan Song0Xinyu Xia1Temair Shorty2Tongtong Li3Amy O. Stevens4Chao Zhao5Yi He6Department of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USADepartment of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USADepartment of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USADepartment of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USADepartment of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USADepartment of Chemical and Biological Engineering, University of Alabama, Tuscaloosa, AL 35487, USADepartment of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USATetrodotoxin (TTX), a potent Site-1 sodium channel blocker (S1SCB), offers highly effective local anesthetic properties with minimal addiction potential. To fully leverage TTX’s capabilities as a local anesthetic, it is crucial to develop a drug delivery system that balances its systemic toxicity with its therapeutic efficacy. Recent studies have shown that peptide mixtures, derived from fragments of Site-1 sodium channel proteins and enhanced with hydrophobic tails (designated MP1 and MP2), can self-assemble into nanostructures that exhibit remarkable sustained-release capabilities for TTX. Despite the profound impact that the addition of a hydrophobic tail has on altering the release behavior of the original peptides, the atomic-level interactions and mechanisms underlying this phenomenon remain poorly understood. In this study, a combination of ColabFold and molecular dynamics (MD) simulations were used to investigate the binding interactions between TTX and the nanostructures formed by MP1 and MP2 at an atomic level. Our findings agree with experimental observations and indicate that the MP1/MP2 nanostructure demonstrates greater stability and higher binding affinity for TTX compared to their non-modified counterparts, P1 and P2. The analysis of the simulations revealed that charged amino acids, specifically aspartic acid (ASP) and glutamic acid (GLU), on the peptides are crucial for strong TTX binding and serve as the primary functional sites. Additionally, the stability of the nanostructure significantly affects TTX binding affinity, elucidating why P1, P2, MP1, and MP2 exhibit different binding capabilities despite containing identical charged residues. The results reported here may provide fundamental information to drive future research and enhance the development of TTX-based drug delivery systems.https://www.mdpi.com/1420-3049/30/1/61tetrodotoxin (TTX)Site-1 sodium channel blocker (S1SCB)local anestheticspeptide-based nanostructuressustained-release drug deliverymolecular dynamics simulations |
| spellingShingle | Shenghan Song Xinyu Xia Temair Shorty Tongtong Li Amy O. Stevens Chao Zhao Yi He Molecular Dynamics Insights into Peptide-Based Tetrodotoxin Delivery Nanostructures Molecules tetrodotoxin (TTX) Site-1 sodium channel blocker (S1SCB) local anesthetics peptide-based nanostructures sustained-release drug delivery molecular dynamics simulations |
| title | Molecular Dynamics Insights into Peptide-Based Tetrodotoxin Delivery Nanostructures |
| title_full | Molecular Dynamics Insights into Peptide-Based Tetrodotoxin Delivery Nanostructures |
| title_fullStr | Molecular Dynamics Insights into Peptide-Based Tetrodotoxin Delivery Nanostructures |
| title_full_unstemmed | Molecular Dynamics Insights into Peptide-Based Tetrodotoxin Delivery Nanostructures |
| title_short | Molecular Dynamics Insights into Peptide-Based Tetrodotoxin Delivery Nanostructures |
| title_sort | molecular dynamics insights into peptide based tetrodotoxin delivery nanostructures |
| topic | tetrodotoxin (TTX) Site-1 sodium channel blocker (S1SCB) local anesthetics peptide-based nanostructures sustained-release drug delivery molecular dynamics simulations |
| url | https://www.mdpi.com/1420-3049/30/1/61 |
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