Molecular dynamics simulation of interaction of lysine dendrimer and Semax peptide

Peptide drug delivery systems development is one of the most important tasks in modern pharmacology. Therapeutic peptides are efficient and have minimum side effects. Parenteral route of peptide administration is the most... [ view full abstract ]

Peptide drug delivery systems development is one of the most important tasks in modern pharmacology. Therapeutic peptides are efficient and have minimum side effects. Parenteral route of peptide administration is the most effective. The main problem in oral route is the action of proteolytic enzymes on peptides and their low mucosal permeability. It is proposed to use dendrimers to solve the problem. Dendrimer is a macromolecule with a symmetrical branched structure. It has stable charge and size. Dendrimers reduce toxic effect of peptides and ensure targeted delivery into cells (e.g., cancer). In some cases, dendrimers with drugs complexes have a much more pronounced therapeutic effect. The regulatory peptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) as a model one was chosen. It has an antioxidant, antihypoxic and neuroprotective effects. It is used for acute ischemic stroke prevention, traumatic brain injury, diseases of optic nerve and glaucoma optic neuropathy treatment, during rehabilitation after stroke.
Currently, method of molecular dynamics is the main method of polymer complexes and biopolymer systems modelling. The simulation was performed via this method for systems consisting of one lyzine dendrimer molecule (32 NH3+ groups), 8, 16 and 24 Semax molecules, water and chloride counterions in a cubic cell with periodic boundary conditions. Further energy minimizations and simulations using GROMACS 4.5.6 package and AMBER_99SB-ildn force fields were performed. The potential energy of this force field consists of valence bonds and angles deformation energy, angles of internal rotation, Van der Waals and electrostatic interactions.
Complexes with peptides were formed in 30-60 ns. The equilibrium size and anisotropy of the complexes were close. Radial distribution of atom number shows that dendrimer was inside, and peptides mainly on the surface of complexes. Hydrogen bonds and ion pairs number of the third and the second complexes were less because of the less close contact between dendrimers and peptides. It is shown that dendrimer of third generation can attach about 22 Semax molecules.

Keywords: dendrimers, peptides, computer simulation, molecular dynamics method.