Shuhei Kawamoto

Inverted micelle formation of cell-penetrating peptide studied by coarse-grained simulation: Importance of attractive force between cell-penetrating peptides and lipid head group

Arginine-rich peptide and Antennapedia are cell-penetrating peptides (CPPs) which have the ability to permeate plasma membrane. Deformation of the plasma membrane with CPPs is the key to understand permeation mechanism. We investigate the dynamics of CPP and the lipid bilayer membrane by coarse-grained simulation. We found that the peptide makes inverted micelle in the lipid bilayer membrane, when the attractive potential between the peptide and lipid heads is strong. The inverted micelle is formed to minimize potential energy of the peptide. For vesicle membrane, the peptide moves from the outer vesicle to the inner vesicle through the membrane. The translocation of the peptide suggests inverted micelle model as a possible mechanism of CPPs.

Coarse-grained molecular dynamics study of membrane fusion: Curvature effects on free energy barriers along the stalk mechanism

The effects of membrane curvature on the free energy barrier for membrane fusion have been investigated using coarse-grained molecular dynamics (CG-MD) simulations, assuming that fusion takes place through a stalk intermediate. Free energy barriers were estimated for stalk formation as well as for fusion pore formation using the guiding potential method. Specifically, the three different geometries of two apposed membranes were considered: vesicle-vesicle, vesicle-planar, and planar-planar membranes. The free energy barriers for the resulting fusion were found to depend importantly on the fusing membrane geometries; the lowest barrier was obtained for vesicular membranes. Further, lipid sorting was observed in fusion of the mixed membranes of dimyristoyl phosphatidylcholine and dioleoyl phosphatidylethanolamine (DOPE). Specifically, DOPE molecules were found to assemble around the stalk to support the highly negative curved membrane surface. A consistent result for lipid sorting was observed when a simple continuum model (CM) was used, where the Helfrich energy and mixing entropy of the lipids were taken into account. However, the CM predicts a much higher free energy barrier than found using CG-MD. This discrepancy originates from the conformational changes of lipids, which were not considered in the CM. The results of the CG-MD simulations reveal that a large conformational change in the lipid takes place around the stalk region, which results in a reduction of free energy barriers along the stalk mechanism of membrane fusion.

A guiding potential method for evaluating the bending rigidity of tensionless lipid membranes from molecular simulation.

A new method is proposed to estimate the bending rigidity of lipid membranes from molecular dynamics simulations. An external cylindrical guiding potential is used to impose a sinusoidal deformation to a planar membrane. The bending rigidity is obtained from the mean force acting on the cylinder by calibrating against a discretized Helfrich model that accounts for thermal fluctuations of the membrane surface. The method has been successfully applied to a dimyristoyl phosphatidylcholine bilayer simulated with a coarse-grained model. A well-converged bending rigidity was obtained for the tension-free membrane and showed reasonable agreement with that obtained from the height fluctuation spectrum.

Precise calculation of the local pressure tensor in Cartesian and spherical coordinates in LAMMPS

An accurate and efficient algorithm for calculating the 3D pressure field has been developed and implemented in the open-source molecular dynamics package, LAMMPS. Additionally, an algorithm to compute the pressure profile along the radial direction in spherical coordinates has also been implemented. The latter is particularly useful for systems showing a spherical symmetry such as micelles and vesicles. These methods yield precise pressure fields based on the Irving–Kirkwood contour integration and are particularly useful for biomolecular force fields. The present methods are applied to several systems including a buckled membrane and a vesicle.

Binding of Tat peptides on DOPC and DOPG lipid bilayer membrane studied by molecular dynamics simulations

Cell-penetrating peptides (CPPs) have an ability of internalisation to inner cells through plasma membrane. The plasma membrane and lipid bilayer in experiments contain negatively charged lipids. HIV-1 Tat peptide, which is one of the CPPs, has many arginines with positive charge, and strongly interacts with negatively charged lipids. We investigate the difference between neutral lipids, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and negatively charged lipids, 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DOPG), by all-atom molecular dynamics simulations. We found that the speed of binding of Tat to lipid membrane for DOPC is more than 10 times faster than the speed for DOPG. The Tat peptides bind to the lipid membrane by attractive interaction between arginine in Tat and phosphates in lipids. Comparing the number of phosphates binding to arginine, DOPG gives a larger number than DOPC. The differences indicate the importance of negatively charged lipids for the investigation of the property of CPPs.

Molecular dynamics study on entrainment phenomenon in model molecular systems

The usual molecular dynamics (MD) simulation adopts a non-liner term (friction force) in the equation of motion to control the system temperature. Since such equation of motion is similar to the van der Pol equation, the synchronization motion could be induced by the particle interactions in some cases. In this study, we carried out the MD simulations of the model diatomic molecules in the gas and solution systems to investigate a possible synchronization phenomenon of molecules. The synchronization of vibrational motions of two diatomic molecules was observed in the gas system when the system temperature was controlled by thermostat. In the case of solution system, the synchronization of two molecules was found to depend on the density of solvent particles. These findings indicate that the synchronization of vibrational motion should be induced by the thermostat and the molecular interaction with surrounding solvent and solute molecules.