Structure, Stability and Molecular Dynamics Study of Bio-Nanotubes
The objective of this project was to develop a structurally stable cyclic peptide nanotube and investigate its behavior in aqueous and lipid environments. Cyclic peptide nanotubes are synthetic proteins/peptides that act as ion or water channels, and are formed by the arrangement of cyclic peptide rings. These nanotubes are biodegradable and biocompatible, making them potential candidates for drug delivery and transportation in the medical field. One advantage of peptide nanotubes over inorganic nanotubes and vesicles is their ability to manipulate the charge, hydrophobicity, and hydrophilicity without chemical substitutions. However, designing structurally and functionally stable cyclic peptide nanotubes is a challenging task that often requires multiple trial-and-error methods. The primary stability of the nanotube is determined by the hydrogen bonds between adjacent rings in the backbone of the channel. In this study, we have successfully designed two stable cyclic peptide nanotubes: 8 × ([D-Leu-L-Lys-(D-Gln-L-Ala)3]) and 8 × [Cys–Gly–Met–Gly]2. Our findings indicate that the structural stability of the channel depends not only on the hydrogen bonds between adjacent rings but also on non-bonded interaction energies, such as electrostatic and van der Waals forces between the side chains of neighboring rings. We discovered that repulsive electrostatic interactions alone can disrupt backbone hydrogen bonds and lead to channel disassembly. Additionally, the stability of the nanotube is influenced by the surrounding environment, including lipid composition and the presence of other charged molecules.
Remarkably, the 8 × [Cys–Gly–Met–Gly]2 nanotube demonstrated exceptional stability for up to one microsecond in various lipid environments, including POPA (1-palmitoyl-2-oleoyl-sn-glycero3-phosphatidic acid), POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), POPC (1-palmitoyl2-oleoyl-snglycero-3-phosphocholine), POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol), and POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine).
The presence of a sulfur bond between adjacent rings significantly enhanced the structural stability of the nanotube in both aqueous and lipid bilayer environments. Furthermore, the incorporation of modified side chains with oppositely charged moieties in adjacent rings also contributes to the stabilization of the channel in both environments. By elucidating the design principles and stability factors of cyclic peptide nanotubes, this study contributes to the development of novel nanomaterials with potential applications in various fields, particularly drug delivery and transport systems. Further investigations are required to explore the functional properties and performance of these stable nanotubes in practical applications to validate their utility and efficacy.
Development of plant based therapeutic against mycotoxins and modulation of CP450 and AChE enzymes
In this study, we aimed to investigate the dynamics of acetylcholinesterase (AChE) and cytochrome P450 (CYP450) enzymes and their inhibitory effects on mycotoxins using a comprehensive approach combining all-atom molecular dynamics simulations,in vitro experiments, and in vivo studies. Mycotoxins, toxic secondary metabolites produced by certain fungi that contaminate food and feed crops, have been implicated in various health issues, including neurological disorders and disrupted drug metabolism. AChE and CYP450 are crucial regulators of acetylcholine levels and drug metabolism, respectively. Our study focused on elucidating the mechanisms by which mycotoxins inhibit these enzymes, employing in vitro assays with cell culture models and animal studies to assess the resultant tissue- and organ-level damage. Notably, we observed enzyme inhibition along with other detrimental effects, such as lipid peroxidation, loss of mitochondrial potential, and cell death. Animal models have demonstrated significant damage to vital organs including the brain, liver, and kidneys. To gain further insight into the inhibition mechanisms, all-atom molecular dynamics simulations were performed. These simulations provided valuable information on the structural dynamics and interactions between mycotoxins and target enzymes, shedding light on the inhibitory processes at the atomic level. Additionally, we screened several plant-extracted molecules to identify potential antagonists of mycotoxin-mediated inhibition. Through rigorous evaluation, we successfully identified specific plant-derived compounds that demonstrated promising antagonistic effects against the inhibitory actions of mycotoxins. Overall, this research project deepened our understanding of the dynamic behavior of AChE and CYP450 enzymes, the inhibitory effects of mycotoxins, and the associated tissue- and organ-level damage. Moreover, our investigation of plant-extracted molecules revealed potential candidates for the development of therapeutics to mitigate mycotoxin-induced enzyme inhibition.