Song Shenghan, Xia Xinyu, Shorty Temair, Li Tongtong, Stevens Amy O, Zhao Chao, He Yi
Department of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USA.
Department of Chemical and Biological Engineering, University of Alabama, Tuscaloosa, AL 35487, USA.
Molecules. 2024 Dec 27;30(1):61. doi: 10.3390/molecules30010061.
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.
河豚毒素（TTX）是一种强效的1型钠通道阻滞剂（S1SCB），具有高效的局部麻醉特性，成瘾潜力极小。为了充分发挥TTX作为局部麻醉剂的能力，开发一种能平衡其全身毒性和治疗效果的药物递送系统至关重要。最近的研究表明，源自1型钠通道蛋白片段并带有疏水尾增强的肽混合物（命名为MP1和MP2）可以自组装成纳米结构，这些纳米结构对TTX具有显著的缓释能力。尽管添加疏水尾对改变原始肽的释放行为有深远影响，但这种现象背后的原子水平相互作用和机制仍知之甚少。在本研究中，结合使用ColabFold和分子动力学（MD）模拟在原子水平上研究TTX与由MP1和MP2形成的纳米结构之间的结合相互作用。我们的发现与实验观察结果一致，表明与未修饰的对应物P1和P2相比，MP1/MP2纳米结构对TTX表现出更高的稳定性和更高的结合亲和力。模拟分析表明，肽上的带电荷氨基酸，特别是天冬氨酸（ASP）和谷氨酸（GLU），对于与TTX的强结合至关重要，并作为主要功能位点。此外，纳米结构的稳定性显著影响TTX结合亲和力，阐明了为什么P1、P2、MP1和MP2尽管含有相同的带电荷残基，但仍表现出不同的结合能力。此处报道的结果可能为推动未来研究和加强基于TTX的药物递送系统的开发提供基础信息。
