Biomaterial Database

Insights into membrane translocation of the cell-penetrating peptide pVEC from molecular dynamics calculations. 2016

Begum Alaybeyoglu, and Berna Sariyar Akbulut, and Elif Ozkirimli

a Chemical Engineering Department , Bogazici University , Bebek, 34342 Istanbul , Turkey.

Discovery of cargo carrying cell-penetrating peptides has opened a new gate in the development of peptide-based drugs that can effectively target intracellular enzymes. Success in application and development of cell-penetrating peptides in drug design depends on understanding their translocation mechanisms. In this study, our aim was to examine the bacterial translocation mechanism of the cell-penetrating pVEC peptide (LLIILRRRIRKQAHAHSK) using steered molecular dynamics (SMD) simulations. The significance of specific residues or regions for translocation was studied by performing SMD simulations on the alanine mutants and other variants of pVEC. Residue-based analysis showed that positively charged residues contribute to adsorption to the lipid bilayer and to electrostatic interactions with the lipid bilayer as peptides are translocated. Translocation takes place in three main stages; the insertion of the N-terminus into the bilayer, the inclusion of the whole peptide inside the membrane and the exit of the N-terminus from the bilayer. These three stages mirror the three regions on pVEC; namely, the hydrophobic N-terminus, the cationic midsection, and the hydrophilic C-terminus. The N-terminal truncated pVEC, I3A, L5A, R7A mutants and scramble-pVEC make weaker interactions with the lipids during translocation highlighting the contribution of the N-terminal residues and the sequence of the structural regions to the translocation mechanism. This study provides atomistic detail about the mechanism of pVEC peptide translocation and can guide future peptide-based drug design efforts.

UI	MeSH Term	Description	Entries
D008051	Lipid Bilayers	Layers of lipid molecules which are two molecules thick. Bilayer systems are frequently studied as models of biological membranes.	Bilayers, Lipid,Bilayer, Lipid,Lipid Bilayer
D008968	Molecular Conformation	The characteristic three-dimensional shape of a molecule.	Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D010455	Peptides	Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are considered to be larger versions of peptides that can form into complex structures such as ENZYMES and RECEPTORS.	Peptide,Polypeptide,Polypeptides
D011485	Protein Binding	The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.	Plasma Protein Binding Capacity,Binding, Protein
D002462	Cell Membrane	The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.	Plasma Membrane,Cytoplasmic Membrane,Cell Membranes,Cytoplasmic Membranes,Membrane, Cell,Membrane, Cytoplasmic,Membrane, Plasma,Membranes, Cell,Membranes, Cytoplasmic,Membranes, Plasma,Plasma Membranes
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D054730	Protein Interaction Domains and Motifs	Protein modules with conserved ligand-binding surfaces which mediate specific interaction functions in SIGNAL TRANSDUCTION PATHWAYS and the specific BINDING SITES of their cognate protein LIGANDS.	Protein Interaction Domains,Protein Interaction Motifs,Binding Motifs, Protein Interaction,Protein Interaction Binding Motifs,Protein-Protein Interaction Domains,Domain, Protein Interaction,Domain, Protein-Protein Interaction,Domains, Protein Interaction,Domains, Protein-Protein Interaction,Motif, Protein Interaction,Motifs, Protein Interaction,Protein Interaction Domain,Protein Interaction Motif,Protein Protein Interaction Domains,Protein-Protein Interaction Domain
D056004	Molecular Dynamics Simulation	A computer simulation developed to study the motion of molecules over a period of time.	Molecular Dynamics Simulations,Molecular Dynamics,Dynamic, Molecular,Dynamics Simulation, Molecular,Dynamics Simulations, Molecular,Dynamics, Molecular,Molecular Dynamic,Simulation, Molecular Dynamics,Simulations, Molecular Dynamics
D057846	Cell-Penetrating Peptides	Peptides that have the ability to enter cells by crossing the plasma membrane directly, or through uptake by the endocytotic pathway.	Cell Penetrating Peptide,Cell-Penetrating Peptide,Peptides, Cell-Penetrating,Cell Penetrating Peptides,Penetrating Peptide, Cell,Peptide, Cell Penetrating,Peptide, Cell-Penetrating,Peptides, Cell Penetrating
D057927	Hydrophobic and Hydrophilic Interactions	The thermodynamic interaction between a substance and WATER.	Hydrophilic Interactions,Hydrophilic and Hydrophobic Interactions,Hydrophilicity,Hydrophobic Interactions,Hydrophobicity,Hydrophilic Interaction,Hydrophilicities,Hydrophobic Interaction,Hydrophobicities,Interaction, Hydrophilic,Interaction, Hydrophobic,Interactions, Hydrophilic,Interactions, Hydrophobic