Molecular Dynamics Simulation of the Complex of PDE5 and Evodiamine.

Alzheimer's disease is an irreversible neurological disorder for which there are no effective small molecule therapeutics. A phosphodiesterase 5 (PDE5) inhibitor is a candidate medicine for the treatment of Alzheimer's disease. Rutaecarpine, an indole alkaloid found in Euodiae Fructus, has inhibitory activity for PDE5. Euodiae Fructus contains more evodiamine than rutaecarpine. Therefore, we performed molecular dynamics simulations of the complex of PDE5 and evodiamine. The results showed that the PDE5 and (-)-evodiamine complexes were placed inside the reaction center compared to the case of PDE5 and (+)-evodiamine complex. The binding of (-)-evodiamine to PDE5 increased the root-mean-square deviation and radius of gyration of PDE5. In the PDE5 with (-)-evodiamine complex, the value of the root-mean-square fluctuation of the M-loop, which is thought to be important for activity, increased. This result suggests that (-)-evodiamine may have inhibitory activity.

Dissipative Particle Dynamics Simulations for Shape Change of Growing Lipid Bilayer Vesicles.

The characteristic shape changes observed in the growth and division of L-form cells have been explained by several theoretical studies and simulations using a vesicle model in which the membrane area increases with time. In those theoretical studies, characteristic shapes such as tubulation and budding were reproduced in a non-equilibrium state, but it was not possible to incorporate deformations that would change the topology of the membrane. We constructed a vesicle model in which the area of the membrane increases using coarse-grained particles and analyzed the changes in the shape of growing membrane by the dissipative particle dynamics (DPD) method. In the simulation, lipid molecules were added to the lipid membrane at regular time intervals to increase the surface area of the lipid membrane. As a result, it was found that the vesicle deformed into a tubular shape or a budding shape depending on the conditions for adding lipid molecules. This suggests that the difference in the place where new lipid molecules are incorporated into the cell membrane during the growth of L-form cells causes the difference in the transformation pathway of L-form cells.

Effect of particles with repulsive interactions enclosed in both rigid spherical shells and flexible fluid vesicles studied by Monte Carlo simulation.

Experimental observations indicate that the repulsion of particles is a factor that induces the transformation of vesicles containing multiple particles. Metropolis Monte Carlo simulations are performed with two models in which repulsive particles are enclosed inside a vesicle. The distribution of the particles and the effective bending coefficient and surface tension of the membrane are analyzed. The shape and internal structure of the vesicle containing the particles are investigated as the vesicle volume is decreased. It is revealed that the repulsive interaction between particles produces a layered structure and stiffens the membrane. When particles repulsively interact over a long range, the membrane takes on a dumbbell form.

Structural Study of Cell Attachment Peptide Derived from Laminin by Molecular Dynamics Simulation.

Peptides with cell attachment activity are beneficial component of biomaterials for tissue engineering. Conformational structure is one of the important factors for the biological activities. The EF1 peptide (DYATLQLQEGRLHFMFDLG) derived from laminin promotes cell spreading and cell attachment activity mediated by α2ß1 integrin. Although the sequence of the EF2 peptide (DFATVQLRNGFPYFSYDLG) is homologous sequence to that of EF1, EF2 does not promote cell attachment activity. To determine whether there are structural differences between EF1 and EF2, we performed replica exchange molecular dynamics (REMD) simulations and conventional molecular dynamics (MD) simulations. We found that EF1 and EF2 had ß-sheet structure as a secondary structure around the global minimum. However, EF2 had variety of structures around the global minimum compared with EF1 and has easily escaped from the bottom of free energy. The structural fluctuation of the EF1 is smaller than that of the EF2. The structural variation of EF2 is related to these differences in the structural fluctuation and the number of the hydrogen bonds (H-bonds). From the analysis of H-bonds in the ß-sheet, the number of H-bonds in EF1 is larger than that in EF2 in the time scale of the conventional MD simulation, suggesting that the formation of H-bonds is related to the differences in the structural fluctuation between EF1 and EF2. From the analysis of other non-covalent interactions in the amino acid sequences of EF1 and EF2, EF1 has three pairs of residues with hydrophobic interaction, and EF2 has two pairs. These results indicate that several non-covalent interactions are important for structural stabilization. Consequently, the structure of EF1 is stabilized by H-bonds and pairs of hydrophobic amino acids in the terminals. Hence, we propose that non-covalent interactions around N-terminal and C-terminal of the peptides are crucial for maintaining the ß-sheet structure of the peptides.

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.

Solvent flow patterns fluctuating largely around a protein and correlation with solvent density fluctuations: A molecular dynamics study.

The authors demonstrated recently that translational motions of water molecules around a protein are collective in a short (approximately 10 ps) time scale. The patterns can be regarded as "flows" of three specific patterns-fair current, drying/wetting, and vortex-although the patterns disappear eventually over a longer time scale. Our earlier study suggested a hypothesis that the solvent flows are related to the intersolute interaction. However, the connection between the flows and the interaction was left unexamined. The current simulation study analyzed flow patterns around a protein, human lysozyme, revealing that the drying flows correlate with decreased solvent density. The decrease in solvent density has been known to enhance intersolute attractive interactions. The drying flows can therefore induce the intersolute attractive interactions. Human lysozyme has a catalytic cleft on the protein surface. Large fluctuations of drying/wetting patterns were observed only around the cleft because the large fluctuations occur selectively around convex residues on the protein surface, to which large side-chain fluctuations of the protein are also assigned. The emergence of fair current patterns correlated well with the emergence of drying/wetting patterns. This correlation was found only near the protein surface. Near the protein surface, the vortex flow plane of rotation tended to be parallel to the surface. Current study suggests that the drying flows enhance the substrate approach to the catalytic cleft.