Kimikazu Sugimori

The Potentials of the Atoms around Mg 2+ in the H-ras GTP and GDP Complexes

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.

Solvent site-dipole fields around guanine nucleotides in the Hras-GTP complex and in the Hras-GDP complex

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.

Analysis of water molecules around GTP in Hras-GTP complex and GDP in Hras-GDP complex by molecular dynamics simulations

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 molecules and oxygen atom of the most distant phosphate from guanosine. We find that these hydrogen bonds are formed. We also find that the oxygen atom of hydrogen bond is determined by the position of the water molecule of hydrogen bond.

Theoretical model for assessing properties of local structures in metalloprotein

For model structures containing two aromatic rings such as the indole of Trp5 and the imidazole of His64 in human carbonic anhydrase (hCAII), the location and orientation of the rings with regard to each other contribute to the magnitude of the entire interaction energy. Here the energetic contribution of the indole ring of Trp5 on the imidazole ring of the “out” conformation of His64 were calculated to compare with that of the alternative “in” conformation of His64 by using the MP2/6-311++G(d,p)//B3LYP/6-31G(d,p) method. We suggest that 1) Trp5 and the “out” conformation of His64 are predicted to form a stack of planar parallel rings via π-stacking interaction and 2) the energy is 1.73-1.83 kcal/mol to stabilize the “out” conformation, compared with the “in” conformation.

Π-stacking Interaction between Heterocyclic Rings in a Reaction Field of Biological System

Reaction fields in biological systems are given by surrounding structures where various interactions such as hydrogen bonding, van der Waals, and π-stacking interaction. However, there is no experimental method to evaluate the interaction energy. Recently, computational techniques have been used as a standard method in order to estimate the interaction energy or to verify the experimental results. Here, we are focusing on the π-electrons, p-orbitals, and conjugate systems in relation to the π-stacking interaction between heterocyclic rings in the reaction field: the active site of human carbonic anhydrase II (HCA II). The electron correlation interaction was calculated on the basis of the Moller-Plesset perturbation theory. Since the His64 has two conformations in the HCA II, the rotational motion of His64 has been used to explain the catalytic mechanism of HCA II. The calculated results indicate that the -stacking interaction stabilizes the structure and restrict the rotational motion of His64.

Network of Water Molecules Around Guanine Nucleotide in the Hras-GTP and -GDP Complexes by MD Simulations

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.

Analysis of Water Molecules in the Hras-GTP and GDP Complexes with Molecular Dynamics Simulations

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.

A molecular dynamics study of Hras-GTP and GDP complexes: The properties of water molecules around guanine nucleotide

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...

An approach to water molecule dynamics associated with motion of catalytic moiety

A water bridge composed of several water molecules between the catalytic moieties, His64 and the zinc-bound solvent, in human carbonic anhydrase II (hCAII) is disrupted when the inhibitor acetazolamide (ACZ) binds to the zinc ion, according to the crystallographic structure of the ACZ-hCAII complex. In this structure, the ACZ methyl group is far (∼10 A) from the His64. However, this binding causes an 1H NMR chemical shift change (∼1 ppm) in His64 in solution. This suggests two alternative mechanisms: a) the ACZ methyl group may be closer to His64 in the complex in solution, compared to the crystal, or b) the disruption of the water bridge might cause the His64 to move or behave in a different manner. The binding of ACZ to the enzyme in solution was examined by observing the NMR signals of the 13C-labeled ACZ methyl group in the ACZ-hCAII complex. The 13C signals of the free and bound forms were detected. In the bound form, the signal for the acetamide group was pH dependent, whereas the sulfonamide group ...

Mathematical model and computer simulation of text reproduction based upon “Quantity Rather Than Quality” concept

Generally, in universities it is ordinary that a small number of experts of the note taking support the hearing impaired because of the difficulty of taking a note simultaneously with hearing a lecture. The purpose of this research project is to construct a new note taking system, namely, the note taking system based upon “Quantity Rather Than Quality” concept. The origin of the name of our system is that in our system many beginners of the note taking, who is an alternative way of a skilled note taker, type the text data and finally reproduce the lecture note with the similar quality as experts do. In this study, we present the mathematical model of our note taking system. We confirm that the increase of the number of people brings the improvement of the accuracy of the input result, and the increase of the probability of correct input brings the expectation value of probability under fixing the number of persons. Finally, we give the results of computer simulation of the model and discuss the feasibility of our concept in detail.