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Hras protein is an intermediate for signals of cell proliferation and cell differentiation when Hras combines with guanosine triphosphate (GTP). In ordinary cells, GTP combined with Hras is hydrolyzed to guanosine diphosphate (GDP), and the structures of the protein-ligand complex strongly depend on hydrogen bonds. In such a system, hydrogen bonds exist between protein and ligand, between protein and water, and between ligand and water. In this study, we applied a relaxation mode analysis (RMA) to the trajectories of MD simulations for Hras-GTP/GDP to investigate the relationship between the dynamics of structures and those of hydrogen bonds. Different relaxation time of relaxation modes of Hras structures and Hras-solvent water hydrogen bonds were evident between Hras-GTP and Hras-GDP, and the results imply that the structure of Hras in Hras-GTP is stiffer than that in Hras-GDP. The method devised here and its interpretation can be applied to other systems focusing on objects with different stiffnesses.

Proteins that specifically bind to metals have been used for research on development of new organic-inorganic hybrid materials. Several peptides and proteins that bind to metals have been reported; this property can be attributed to their structures. In this paper, we assessed the binding of a sequence of the protein called LARFH to a metal surface. We performed simulation with several models of LARFH protein with different loop sequences binding to the metal surface. It was found that the angle between the LARFH protein and the metal surface varied for different loop sequences. We also performed simulations of the detachment process of LARFH. It was concluded that the stronger binding to metal is established by two gold-binding loops of the LARFH sequences.

Chemerin-9 is a nonapeptide that corresponds to the YFPGQFAFS sequence on the C-terminus of Chemerin protein. Recent clinical and animal studies using mice, it has been recently reported that Chemerin-9 binds to the ChemR23 receptor and can suppress the inflammation-related diseases such as arteriosclerosis.In this study, molecular dynamics simulations were performed with the Chemerin-9 peptide to identify structures with high and low free energy. Docking simulations of these structures of Chemerin-9 and ChemR23 receptor were performed, and the docking model with the lowest free energy and binding energy of Chemerin was identified. For this model, the binding sites and binding forces were evaluated. Based on these findings, we aim to provide insights into the development of new drugs that suppress arteriosclerosis.

We computationally examined the structure of anti-tumour bicyclic hexapeptide RA-VII. This peptide adopts three conformations (confs.), A, B and C, in dimethyl sulfoxide (DMSO). Although it was exp...

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.

Mutations in the FHL1 gene can cause X-linked hereditary myopathy, which causes one of the rarest intractable diseases. The age of the disease onset is quite variable from early infancy to adulthood, and the patients show progressive muscle weakness and atrophy. The FHL1 protein is constituted by four and a half LIM domains. Each LIM domain contains two zinc fingers, which contribute to the structural stability of the LIM domain. A change in the cysteine or histidine residues in the 2nd LIM domain (LIM2) is closely associated with the disease severity. Therefore, LIM2 is suggested to have an essential role in maintaining the structure of FHL1. In this study, molecular dynamics simulation was performed on molecular models consisting of LIM1 and LIM2 of wild and mutant FHL1. We calculated the extent of distortion of zinc finger structure and measured the distance between zinc atom and Cα atom of zinc-coordinated residues. Our analysis showed that the correlation between these two quantities is larger in the mutants associated with severe myopathy.

Artificial creation of fibers utilizing proteins has been a target of bionanotechnology. Yagi et al. succeeded in designing artificial protein fibers using two types of proteins: LARFH and sulerythrin. Binding interfaces were designed for sulerythrin and LARFH by introducing mutations, and the fibrous structures were confirmed by atomic force microscopy. However, branching was observed in the fibrous structure, possibly because of non-specific interactions between the proteins. In this study, we analyzed the behavior and binding sites of sulerythrin mutants and LARFH mutants using coarse-grained molecular dynamics (MD) simulation. Binding simulations were performed for a system of one sulerythrin and one LARFH, and also of two sulerythrin molecules and four LARFH molecules. These results suggested that glutamic acids originally possessed by sulerythrin contribute to non-specific binding at sites other than the designed interfaces.

Telomeres, which consist of single-, double- and four-stranded DNA, shorten after each round of cell division. The repeated telomeric DNA sequence 5′-TTAGGG-3′ does not encode genetic information and is not replicated completely. We performed molecular dynamics (MD) simulations of telomeric single-stranded DNA (ssDNA) and protection of telomere 1 (POT1) for 100 ns. We calculated the distance between Cα (POT1) and O5’ (telomeric ssDNA) to verify the binding system for 100 ns MD. We then calculated the distance between the bases of the telomeric DNA ends and the root-mean-square deviation and gyration radius in the single and binding states. Moreover, we compared the root-mean-square fluctuations (RMSFs) between the single and binding states and calculated the number of hydrogen bonds between POT1 and telomeric DNA. There are many hydrogen bonds between Gln94 and the first guanine of the closest 5′-TTAGGG-3′ sequence in telomeric single-stranded DNA, and the RMSF between the single and binding states has a large difference between Gln94 and guanine. Overall, we found that Gln94 and guanine are important components of the binding system and are related to the stability of this system. The molecular dynamics simulations of the telomeric single-stranded DNA (ssDNA) and protection of telomere 1 (POT1) in the single and biding states have been performed for 100 ns to compare the structures of those and to calculate root-mean-deviation, gyration radii, root-mean-square fluctuation and the number of hydrogen bonds. We found that the structures of the telomeric ssDNA in the single and binding states are different, and that one guanine and Gln94 are important for the binding system.

The γS-crystallin protein maintains transparency and increases the reflection index of the eye lens. Here, γS−G18V, a mutant of γS-crystallin, was studied, in which the 18th residue, glycine, is replaced by valine. This mutation is associated with childhood-onset cortical cataract. Mutated γS-crystallin forms cross-links with other proteins in the eye lens and leads to aggregation at a temperature lower than that for γS-crystallin. In this study, structural analysis of γS-crystallin and γS−G18V was performed by molecular dynamics simulation. It was found that cysteine residues around the area where the mutation is introduced are arranged at the solvent side with less hydrogen bonds than in the case of γS−WT.

We investigate the structures of the Hras-GTP and the Hras-GDP complexes in water solvents in order to understand the mechanism of GTP hydrolysis in the Hras-GTP complex. We performed MD simulations of these complexes in order to study the positions and the orientations of water molecules around the guanosine nucleotides. Using trajectories we calculated the angular distribution of water molecules around the most distant phosphorus from guanosine in our previous work. It was shown that water molecules are distributed evenly in GTP, although unevenly in GDP. This suggests that the trigger of GTP hydrolysis is possibly the attack of water molecule to γ−phosphate from the appropriate direction. In this paper, in order to investigate the role of water molecules in GTP hydrolysis in detail, we calculate the orientation of water molecules. The distribution of the orientation is different between GTP and GDP. In order to investigate the cause of this difference, we examine the hydrogen bonds between water molecu...

Rational design of protein surface is important for creating higher order protein structures, but it is still challenging. In this study, we designed in silico the several binding interfaces on protein surfaces that allow a de novo protein–protein interaction to be formed. We used a computer simulation technique to find appropriate amino acid arrangements for the binding interface. The protein–protein interaction can be made by forming an intermolecular four-helix bundle structure, which is often found in naturally occurring protein subunit interfaces. As a model protein, we used a helical protein, YciF. Molecular dynamics simulation showed that a new protein–protein interaction is formed depending on the number of hydrophobic and charged amino acid residues present in the binding surfaces. However, too many hydrophobic amino acid residues present in the interface negatively affected on the binding. Finally, we found an appropriate arrangement of hydrophobic and charged amino acid residues that induces a ...

We study the structures of the Hras-GTP complex and the Hras-GDP complex in water to investigate the mechanism of GTP hydrolysis of the Hras-GTP complex. We performed molecular dynamics simulations of these complexes to investigate the structures of these complexes using the potential parameters of AMBER ff03 and our potential parameters around Mg2+. Our simulations show that the averaged structure differences between the Hras-GTP complex and Hras-GDP complex are found in the switch I and II regions. In particular, in the switch II region, the α2-helix of Hras-GDP is shorter than the α2-helix of Hras-GTP. The averaged number of water molecules in the first hydration sphere in Hras-GDP complex is larger than that in Hras-GTP complex. The occurrence ratio of the duration time of waters in the first hydration sphere of PA has long tail both in Hras-GTP and in Hras-GDP. In Hras-GDP complex, β-phosphate is hard to be hydrolyzed, while the number of waters in the first hydration sphere is larger than those in Hras-GTP. This suggests that there is a special direction for the hydrolysis. © 2013 Wiley Periodicals, Inc.

We investigated the deformation of lipid bilayer membrane by cell-penetrating peptide using coarse-grained molecular dynamics simulation. The simulations have been performed with different values of two parameters, strength of angle potential of lipid and strength of attractive interaction between peptide and lipid heads. We obtained the phase diagram of deformation of membrane and found that there are four kinds of structures such as surface dent, inverted micelle, double bilayer, and transmembrane. The results suggest that one peptide can make various structures on lipid bilayer membrane. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012

S-crystallin maintains transparency of the crystalline lens and increases the refraction index of lens. S-G18V is a mutant S-crystallin in which 18th glycine is replaced by valine. This protein is related to childhood-onset cortical cataract. In this paper, we study the fluctuation of residues and dihedral angles, and investigate the difference between S-WT and S-G18V by using molecular dynamics simulation. In the result of RMSF, we found large difference around the mutation point. In addition, differences of dihedral angles of cysteins were found in this area.

We study the early process of gelation using our model of 5 particles and 9 particles in a monomer. We compare our models and obtain slower reaction for model of 9 particles. We also study the effect of random force and obtain slower reaction with random force but more extended structure.

Polymers and proteins have both similarities and differences with conformation and order formation. We perform molecular dynamics simulation of gelation process and also of aggregation of proteins. By discussing the results of the simulation, we obtain some insight into the difference of order formation of polymers and proteins.

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. H...

Laminin is one of the components of the basement membrane and, laminin has diverse biological activities [1-2], such as promotion of cell attachment, cell migration, tumor metastasis, neurite outgrowth and angiogenesis [2]. Previously, Suzuki et al. identified several functional peptides (EF1-EF5) derived from LG4 modules of laminin alpha 1-5 chains [3]. Previous results showed that biological activities of N-terminal and C-terminal truncated peptide of EF1 are enhanced by disulfide bond [3], and the importance of hairpin-like structure was suggested. By contrast, the EF2 does not have biological activity despite the homologous sequence of the EF1 [4]. Based on these results, the relationship between conformation and activity can be suggested. Thus, we perform conformation analysis of EF1 and EF2 using molecular dynamics simulations.

The size of most bacteria is about several micrometers in diameter, and motion of the bacteria is greatly influenced by viscous drag of the surrounding media[1]. Since the inertial motion is strongly restricted in such an environment, these bacteria skillfully use their appendages in order to move freely and autonomously. A common bacterium, e.g. Escherichia coli or Bacillus subtilis, is known to swim in liquid medium or to swarm on semisolid surfaces by rotating its flagella. Other bacterial species crawl over solid surfaces by extending and retracting their multiple pili. This motility is called ”twitching”, of which mechanism has been experimentally investigated on Pseudomonas aeruginosa[2] and Thermus thermophilus[3]. Though the alternating extension and retraction of bacterial pili should control the twitching motility, its mechanical and dynamical properties accompanied by the motion of pili are not fully understood. Here, we present a model of bacterium due to the twitching motility on solid surfaces and investigate characteristics of the bacterial motion by computer simulation (Fig.1). Our model of bacterial motion is based on Stokes’ law. Therefore, the drag force of the bacterial body in the viscous fluid balances with self-propelled force caused by retracting movement of the pili. In our simulation, when the single pilus is released from a surface of the medium, the balance of these forces is suddenly lost and the bacterial body turns in a short time like oversteering. This rapid motion is called ”slingshot” and found first in experiments[4]. According to the experiments, the average velocity of ”slingshot” is examined as ∼ 1.0μm/s which is faster than the retracting speed of the pilus ∼ 0.5μm/s. Thus, we can suggest that in spite of very small Reynolds numbers, bacteria powerfully locomote against a viscous fluid by means of retracting and releasing thier multiple pili to the surfaces skillfully.

protein to study the effect of mutation to the binding sites of protein. We replace original amino acids on the surface by negatively or positively charged amino acids. We also study the effect of solvent to the binding of proteins. Our computational study may be useful for future experimental study of protein bindings. Making nano-fibers with proteins (1-3) is an interesting and challenging field. We have tried to construct nano-fibers while retaining native structure. We started with proteins which form 4-helix bundle structure (4) by two proteins, each having two helices. In our previous studies (5-6) of molecular dynamics simulation of all-atom model, we have found that IPMDH (3-isopropylmalate dehydrogenase) (7-9) is a good candidate for a building unit of constructing nano-fibers because of the high stability of the mutated IPMDH. In this study, we have performed molecular dynamics simulation of coarse-grained model of IPMDH proteins. We have introduced several mutations on the surface of IPMDH and found that the mutated IPMDHs are likely to make larger clusters than the wild-type IPMDH. 2. Simulation Model and Method We used coarse grained model of IPMDH with MARTINI force field (10), where one interaction point represents on average four heavy atoms. There are four kinds of interaction points in MARTINI force field: polar, nonpolar, apolar and charged. Using coarse grained model, we can perform simulation of long-time behavior of large scale system. To check the model, we calculated radial distribution function for both all-atom model and coarse grained model, and obtained similar results.

Designing protein surface to create the functional structure is a challenging target in protein engineering. The objective of this study is to design the binding interface between proteins that form protein-protein interaction. We chose a four-helix bundle motif [1] as a scaffold for the intermolecular interaction. We searched and chose YciF protein as a scaffold where binding interface are to be created by mutation. Based on this motif, we designed several binding interfaces including some charged and hydrophobic amino acid residues.

GTP hydrolysis in Hras-GTP is suppressed in many human tumor cells, and this suppression is caused by structural change of Hras-GTP. We study the structures of Hras-GTP and -GDP complexes with water solvent by MD simulations. We investigate the distributions of the position and the orientation of water molecules around GTP/GDP in Hras-GTP/Hras-GDP. In this paper, it is found that the short time averaged values of orientation of water molecules near GTP are different from those near GDP. Our results suggest that the water molecules, which change the direction more often around GTP than around GDP in the short time, play important roles in GTP hydrolysis in Hras-GTP.

Directional correlation of solvent site-dipole field, resulting from orientational ordering of individual water molecules around guanine nucleotides in the Hras-GTP complex and in the Hras-GDP complex, was studied with molecular dynamics simulations of the Hras-GTP and the Hras-GDP complexes in water solution. The coarse-grained time-window-averaged site-dipole fields are different between Hras-GTP and Hras-GDP at some area, although the time-window-averaged site-dipole fields without spatial coarse-graining are not so different. This suggests that, for the orientation of water molecules at special position, the spatial coherence is more important than the temporal coherence for GTP hydrolysis in the Hras-GTP complex.

Shape transformations of a vesicle during the polymerization of an encapsulated microtubule is studied by the Monte Carlo simulations, and the morphology phase diagram is obtained in the phase spac...

Shapes of a three-dimensional and axially-symmetric vesicle are studied by the Monte Carlo simulation of a joint-segment model. At finite temperatures and pressures, various shapes of a vesicle such as a sphere, a dumbbell, a codocyte-I,II, a torocyte and a rotated triangular-like shape are obtained. The phase diagram at the lowest temperature agrees quantitatively with the one obtained in the ground state by Seifert et al. using the variational calculation of the continuum elastic energy. Dynamical processes of shape transformations are also investigated.

We study the structures of Hras-GTP and Hras-GDP complexes in water in order to investigate the mechanism of hydrolysis of GTP in the Hras-GTP complex. Understanding of the mechanism of hydrolysis of GTP in the Hras-GTP complex plays a key role in overcoming the human cancer. We performed molecular dynamics (MD) simulations of Hras-GTP complex and Hras-GDP complex in water using AMBER03 parameters and our calculated parameters around Mg2+. Using the trajectories of the MD simulations, we calculated the radial distribution functions of water molecules around the phosphorus atoms in guanine nucleotide in each complex. We also calculated the radius of the first hydration sphere, the averaged number of water molecules in the first hydration sphere, and the distribution of duration time of water molecules in the first hydration sphere. We also calculated the distribution of water molecules with respect to the angle around the PG in GTP and PB in GDP. It is suggested that the hydrolysis is triggered by water mo...

In the Hras-GTP and GDP complexes, the coordination bonds between Mg2+ and oxygen atoms are very important. In this study, we use AMBER03 and our calculated force field parameters, and perform MD simulations of Hras-GTP and GDP complexes with water solvents. It is shown that the number of water molecules in the first hydration sphere is larger in GDP than in GTP. The duration time and the direction of water molecules in the first hydration sphere in GTP is not so different from those in GDP. It is shown that water molecules are distributed evenly around PG, although they are not distributed evenly around PB. This difference can be the reason why the hydrolysis of GTP in Hras-GTP is easier than the hydrolysis of GDP in Hras-GDP.

Statistical properties and patterns of bacterial colony formed by the twitching motility are studied from the viewpoint of both computer simulations and experimental examinations. Models of four kinds of bacterial motion are proposed and the growing bacterial colonies due to the models are simulated by means of Monte Carlo method. Macroscopic patterns of the bacterial colonies and orientational order parameters of the bacteria are analyzed. By comparing the simulation results with the colony pattern formed by Thermus thermophilus, we suggest that wriggling edge of the colony is caused by slingshot-like motions of bacteria.

Docking of two protein molecules is induced by intermolecular interactions. Our purposes in this study are: designing binding interfaces on the two proteins, which specifically interact to each other; and inducing intermolecular interactions between the two proteins by mixing them. A 4-helix bundle structure was chosen as a scaffold on which binding interfaces were created. Based on this scaffold, we designed binding interfaces involving charged and nonpolar amino acid residues. We performed molecular dynamics (MD) simulation to identify suitable amino acid residues for the interfaces. We chose YciF protein as the scaffold for the protein-protein docking simulation. We observed the structure of two YciF protein molecules (I and II), and we calculated the distance between centroids (center of gravity) of the interfaces’ surface planes of the molecules I and II. We found that the docking of the two protein molecules can be controlled by the number of hydrophobic and charged amino acid residues involved in the interfaces. Existence of six hydrophobic and five charged amino acid residues within an interface were most suitable for the protein-protein docking.

We study the effect of the tails of H3 and H4 histones in the nucleosomes, where DNA and histones are packed in the form of chromatin. We perform molecular dynamics simulations of the complex of DNA and histones and calculate the mean square displacement and the gyration radius of the complex of DNA and histones for the cases with tails intact and the cases with tails missing. Our results show that the H3 tails are important for the motion of the histones. We also find that the motion of one tail is affected by other tails, although the tails are distanced apart, suggesting the correlated motion in biological systems.

We study a curvature instability of a two-dimensional (2-D) vesicle induced by “ impurities (intercalated molecules)”. Impurity yields the free energy cost proportional to the membrane curvature and the impurity concentration. By simulating a model vesicle with spheres connected with tethered chains, shape transition is observed from ellipse to bi-lobocyte depending on the coupling constant between the vesicular curvature and impurities.

In the field of nanotechnology, a variety of applications have been anticipated. We have been trying to design nano-fibers using proteins while maintaining their native structures. We try to use Lac repressor two-helix protein (LARFH), sulerythrin, and 3-isopropylmalate dehydrogenase (IPMDH) as adaptors for constructing nano-fibers. By making use of the α-helices outside of respective proteins, we are trying to form binding site between proteins: two α-helices of one protein are designed to form four-helix bundle with two α-helices of another protein. In addition, by introducing mutations in amino acids at the binding sites, hydrophobic and electrostatic interactions can be modified. The fiber may be produced upon mixing the two kinds of proteins. By umbrella sampling simulation, we have found that in the combination of LARFH-/-LARFH, hydrophobic interaction is enhanced in wild type, and electrostatic interaction is enhanced in variant. We also found high stability of IPMDH-/-IPMDH.

Cell-penetrating peptides can permeate through the plasma membrane. The permeation ability is useful for delivery of bioactive molecules. Experiments suggest that the binding between the guanidino group in the peptide and lipid headgroups is of crucial importance in the peptide permeation through lipid membranes. We investigate the free energy profile for the permeation of the peptide through the lipid bilayer membrane with changing the binding strength by a series of coarse-grained molecular dynamics simulation. We found that the energy barrier for the permeation has the minimum at the medium strength of the binding (∼2e). Our result suggests that the appropriate attractive interaction between peptide and lipid headgroups enhances the permeation of the peptide across the lipid membranes.

We have studied the quantum state around the Mg2+ ion in the H-ras GTP and H-ras GDP complexes in order to understand the hydrolysis of GTP to GDP in the H-ras complex, which plays a key role in overcoming human cancer. We calculated the force fields and atomic charges around the Mg2+ ion in the H-ras GTP and H-ras GDP complexes at the B3LYP level, using a basis functional set 6-31G**. The calculations were performed in the subsystem consisting of the bases or the molecules containing the oxygen having a coordinate bond to the Mg2+ ion. They showed that the oxygen atoms in both GTP and GDP bind tightly to the Mg2+ ion, although the oxygen atoms in H2O bind loosely. We have also performed MD simulations of the H-ras GTP and H-ras GDP complexes in solution, using these potential parameters. We showed that the structure differences between H-ras GTP and H-ras GDP are found mainly in loop 2 and loop 4.

A two-dimensional vesicle of hard rods subject to a shadowing interaction is analy2ed by Monte Carlo simulations. From the mode analysis of the shape fluctuation of the vesicle, the bending rigidity is estimated microscopically and the relation between the rod length and the bending rigidity is studied. A scaling relation of a mean square radius of gyration is investigated and compared with that proposed by Leibler, Singh and Fisher. Increasing osmotic pressure a vesicle performs a shape transition from a circular to bi-lobocyte shape. A vesicle with a spontaneous curvature is also studied by using molecules of a frustum shape.

The technology of Human Machine Interface (HMI) mainly investigate about how to use machines in a more humanized way so that the communication between human and the machine could become more harmonic and natural. Previous studies indicate that there is an integration area in the human brain for audiovisual information processing. Although machines also possess mechanism for audiovisual processing, there is shortage of audiovisual information integration. And to solve this issue, the prerequisite is to make clear what kinds of cognitive processing characteristics do humans have. In this current Event-Related Potentials (ERPs) study, we adopted a left-and-right-separated sensory modality method to investigate the characteristics of human audiovisual information processing. The results showed that the main audiovisual interactions were found in frontal-central scalp sites around 80–100ms during the early stage and 280–300ms during the later stage of processing. This study provides foundation for understanding the information processing characteristic of human cognitive system and for the future machine humanization.