Recent Advances of Studies on Cell-Penetrating Peptides Based on Molecular Dynamics Simulations

Abstract

With the ability to transport cargo molecules across cell membranes with low toxicity, cell-penetrating peptides (CPPs) have become promising candidates for next generation peptide-based drug delivery vectors. Over the past three decades since the first CPP was discovered, a great deal of work has been done on the cellular uptake mechanisms and the applications for the delivery of therapeutic molecules, and significant advances have been made. But so far, we still do not have a precise and unified understanding of the structure–activity relationship of the CPPs. Molecular dynamics (MD) simulations provide a method to reveal peptide–membrane interactions at the atomistic level and have become an effective complement to experiments. In this paper, we review the progress of the MD simulations on CPP–membrane interactions, including the computational methods and technical improvements in the MD simulations, the research achievements in the CPP internalization mechanism, CPP decoration and coupling, and the peptide-induced membrane reactions during the penetration process, as well as the comparison of simulated and experimental results.

Cell Penetrating Peptides: Classification, Mechanisms, Methods of Study, and Applications

“…Another group has explored the neuroprotective effects of two arginine rich CPPs, containing TAT fragments, by CD experiment aimed to characterize the interaction of these peptides with an artificial neuronal membrane. Modification in the intensity of the peptide CD signal in combination with the redshift effect was symptomatic of the formation of ordered structures during the interaction with neuronal mimicking liposomes [172] . Generally, peptide‐lipid interactions of amphiphilic peptides stabilize their helical structural conformation via hydrophobic forces, [173] inducing an efficient crossing of the membrane.…”

“…Discriminate between internalization within lipid bilayer or surface [170][171][172][173][174][175][176][177][178][179] Electron Microscopy Peptide distribution and membrane modification induced by the peptide.…”

“…Modification in the intensity of the peptide CD signal in combination with the redshift effect was symptomatic of the formation of ordered structures during the interaction with neuronal mimicking liposomes. [172] Generally, peptide-lipid interactions of amphiphilic peptides stabilize their helical structural conformation via hydrophobic forces, [173] inducing an efficient crossing of the membrane. This behavior has been successfully exploited to design a trimeric epsin-peptide able to induce positive curvature and promote loosening of the lipid packing by inserting its hydrophobic moieties into the lipid bilayer.…”

Application of computational approaches in biomembranes: From structure to function

“…Unlike AMPs used for microbial defense, CPPs, and blood–brain barrier‐penetrating peptides (B3PPs) can cross cellular and tissue barriers and deliver various types of molecules, having potential applications in drug delivery, gene therapy, and imaging. Explicit‐solvent MD simulations have been applied to predict the interaction between biomembranes and penetrating peptides, to understand the molecular mechanism of passive penetration, and to accurately assess the energetic and structural preferences of the peptide structures in the aqueous solutions 229–232 . Though promising, the clinical use of these peptides remains constrained by their toxicity and insufficient specificity.…”

“…Explicit-solvent MD simulations have been applied to predict the interaction between biomembranes and penetrating peptides, to understand the molecular mechanism of passive penetration, and to accurately assess the energetic and structural preferences of the peptide structures in the aqueous solutions. [229][230][231][232] F I G U R E 6 The molecular mechanism for butanol tolerance of E. coil's inner and outer membranes. (a) A schematic model illustrating the inner membrane disruption following butanol partitioning, with the representative membrane conformation predicted by MD simulations showing the coexistence of partially interdigitated and splayed phospholipids.…”