We have successfully induced the formation of 17 different organs in vitro from animal caps (undifferentiated or multipotent cells) of Xenopus blastulae and 6 different organs from mice ES cells (Embryonic Stem cell). For the Xenopus embryo, we subsequently have attempted to transplant these in vitro-generated organs into embryos to determine their functional capacity. In three different experiments we induced the formation of a pronephros, eye-ball and beating heart from animal caps variously treated with activin and retinoic acid, and then transplanted these organs into an embryo in which the corresponding rudiment organ had been removed. Results depended on the organs, timing and transplantation positions, but in the case of the eye, the transplanted organ clearly became functional. To determine whether the transplanted in vitro-generated eye was functional, we labeled the egg red using Texas Red dextran-amine or the embryo green by ectopic expression of green fluorescent protein. Then eye formation was induced, and after 3 further days of culture the labeled eye was transplanted into Xenopus embryos in which the presumptive eye had been removed. Within one month of transplantation, histology and electron microscopy showed that nerves from the ectopic eye had innervated the host brain. Over 3 months, tadpoles with the ectopic transplanted eyes developed to young frogs, and the eyes were observed to react to light and other stimuli. These transcription experiments have done with other in vitro-induced organs such as pronephros (kidney) and beating heart. The transplanted organs can function in host embryos like as normal their organs. To expand these basic data, we have tried to use the mice ES cells. After the treatment of specific inducing factors, we have succeeded to make several kinds of organs in vitro, such as heart muscle, smooth muscle, adipocyte, neural cells, gut, pancreas and so on, from mice ES cells. We have examined these in vitro-induced organs from the structural and functional views.

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One of the research projects in post-genome era is to reconstruct the life of living organisms from their genome. Topics given in the present lecture are he development of CE/MS method as a tool of metabolomics, applications of metabolomics to functional genomics, systems biology, simulation of metabolism, and drug design.

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Systematic nomenclatures, linear notations, and connection tables are compared as communication media of organic structures and reactions. Their scope and limitations are discussed from a viewpoint of chemoinformatics for the Internet Age. XyM Notation and XyM Markup Language (XyMML) are proposed as new media, which are inplemented as a TeX/LaTeX application (XyMTeX) for printing and as an XML/XSLT and a Java application (XyM-XSLT and XyMJava) for Web communication. An alternative method via PostScript and PDF is also discussed.

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The three dimensional structures of biopolymer, such as protein and nucleic acid, have been solved by X-ray crystallographic analyses and 2-dimensional NMR. On the other hand, many classical simulations by using empirical energy function were performed. The researches, that are intended to solve the dynamic structure of a biopolymer theoretically, have been increased with progress of computer technology. A biomembrane model and protein, which are surrounded by water molecules and counter ions, can treat now. Although it is in a microscopic moment, the motion is reproducible by using computer graphics. With what accuracy can the function of biomolecules be caught from these simulations? Although the empirical potential function used as the foundation of the simulations is used as black box, how far does the reliability exist? How is the improvement of the potential function made? Here, the practical method of developing the polarization potential which has attracted attention also in calculation of a biopolymer recently at last is described, looking back upon the history of the improvement covering the quarter of a century about empirical energy function.

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Using the perturbation technique developed by Coulson and Longuet-Higgins and the HMO method, one of the authors (H.H) found anomalous but interesting behavior of the π-electron flow called Tunneling Electron Transfer, TET, in large polycyclic aromatic hydrocarbon networks, which the conventional organic electronic theory cannot predict. The effect of the heteroatom substitution appears as Global-type and Local-type depending on the site of substitution. In this study we carried out more elaborated semi-empirical (MNDO, AM1, and PM3) and ab initio molecular orbital (MO) calculations. We compare the electron flow as the change of Mulliken charge of Global-type and Local-type from Parent, which is the unsubstituted polycyclic aromatic hydrocarbon. The behavior of the total electron flow, which was obtained at the higher levels of theory, is in parallel with those of HMO. The contribution to the electron transfer from the σ and π electrons is also discussed. Analysis of the characteristics of energy levels and shapes of the MOs is in progress.

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Molecular dianions/dications of many polycyclic aromatic hydrocarbons (PAHs) have long been regarded as antiaromatics because of their global paratropic pi-electron current. However, many of them are supposed to be aromatic with positive topological resonance energies (TREs). In order to reconcile such energetic and magnetic criteria of aromaticity, we derived a new TRE-like energetic quantity from the magnetic response of the pi-system and called it a magnetic resonance energy (MRE). MRE was found to be highly correlative with TRE for a variety of PAHs and their molecular dianions/dications. We can now discuss energetic and magnetic criteria of aromaticity unambiguously on this theoretical basis. Many PAH dianions/dications indeed turned out to be aromatic with positive MREs even if they exhibit paratropic currents along the periphery of the pi-system.

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Of all the theoretical concepts that constitute the rational basis of modern organic chemistry, the concept of aromaticity is one of the most general, but at the same time one of the most vaguely defined. Generally, aromaticity has been defined as the difference between π-electron resonance energies of a non-cyclic π-conjugated compound and the cyclic π-conjugated compound, giving rise to the (4n + 2)π rule in Huckel molecular orbital (HMO) theory.2 Although the definition of aromaticity on the basis of HMO theory can be readily understood, the treatment of complex compounds such as non-planar molecules remains difficulty. Aromaticity has also been treated magnetically, and Schleyer et al. proposed the nucleus-independent chemical shift (NICS) as an index of aromaticity. The values of the NICS are adequate for classification of aromaticity and anti-aromaticity, but measurement is intensive as shown in previous papers. A new criterion of aromaticity for cyclic π-conjugated compounds is proposed based on CiLC (CI/LMO/CASSCF) analysis founded on ab initio molecular orbital methods. The new criterion states that the all bonds should have equivalent electronic states and the difference between weights for the singlet coupling and polarization terms (from CiLC analysis) should be small. The (4n + 2)π rule of aromaticity for cyclic π-conjugated compounds is reexamined using this new criterion. The criterion is applied to CnHn structures with Dnh (n = 4, 6, 8, and 10) symmetries and their equilibrium structures, and it is demonstrated that the proposed criterion reasonably explains the (4n + 2)π rule. An index of deviation from the aromaticity (IDA) is also defined for comparison of the aromaticity of ring-unit compounds.

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Large-scale computations of temperature- dependent relative stabilities for two isomeric fullerene systems C84 and C94 are carried out at semi-empirical and ab initio MO levels. All C84 IPR isomers are fully optimized at HF/6-31G* level and their harmonic vibration frequencies are calculated by the SAM1 method. The computed energies, structural and vibrational data are employed in the construction of isomeric partition functions and evaluation of the relative Gibbs free energies. The similar Gibbs energy treatment is further applied to C94 IPR isomers. Considerable temperature effects on the relative stabilities and behaviors of enthalpy-entropy interplay in two systems are found and thus good agreements with recent experimental observations are achieved.

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The atomic Schwinger-Dyson(ASD), which is a kind of the treatment of relativistic quantum field theory, is presented for an application to electron and electronic matter. The ASD formalism consists of coupled Dyson equations of an electrons and photons. Because, it includes self-energies in nonperturbative way, higher-order correlations beyond Hartee-Fock approximation are taken into account. Some important differences between the ASD formalism for the system of finite electron density and SD formalism of zero electron density are shown. The main difference is due to the existence of condensed photon field, symmetry breaking, what we call, Coulomb potential. By paying special attention to the treating of the condensed photon fields, the coupled Dyson equations of electron and photon are derived based on functional propagator method. It is shown that this treating of the condensed fields naturally leads to tadopole energy, which cancels Hartree energy. A general representation of photon propagator is derives by using projection operators and by solving an inverse matrix problem. By using these meson propagators, explicit expression of ASD coupled equations and the energy density of matters are derived for numerical calculations in a subsequent paper. Similarities and difference between ASD and traditional methods such as the mean field theory or Hartree-Fock are discussed.

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We make further refinements to the integral equation theory, which is based on the distributed partial wave formulation of the molecular Ornstein-Zernike equation. The theory provides a rigorous and transparent framework for multiple site treatments of molecular fluids. Improvements in the present study consist of the topics: (a) the developments of the orientational-dependent closure relationship using the two-dimensional angular quadrature described by Lebedev, which exactly integrates all spherical harmonics up to a certain degree L, and (b) the renormalized formula for a charged system, which is analogous to the relationship of the extended reference interaction site model (XRISM). We examine the theoretical framework with calculations of some polar and non-polar molecular systems. Our numerical results are compared with the ones predicted by computer simulations and the XRISM theory. The site-site radial distribution functions obtained by the partial wave expansion are more appropriate to reproduce the simulation results than the XRISM ones.

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It is thought that the quick classification of polymer is useful for recycling of resources. Therefore, the quickness and simple distinction using the near infrared spectrum are expected. However, the neural network, one of the distinction methods usually gives us intuitively no clear distinction conditions. Therefore, we searched simple and useful distinction conditions for identifying polymer groups, for example, polyethylene, polystyrene, ABS, and so on by using the classification and regression trees. Consequently, it found out that simple and intelligible distinction could be performed when comparing about 280 polymers. Therefore, the classification chart by near infrared spectra of polymers would be proposed somehow.

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The prediction system of the biodegradation and bioaccumulation of the existing chemical using the structure activity relationships as a part of the existing chemicals for the check of their safety are developed. The prediction system evaluates substructure information automatically from the structural formula inputted on on-line, is classified into similar structure and outputs the prediction value of qualitative biodegradation and bioaccumulation from the flow of the experimental knowledge, or regression analysis. It is premised on using a prediction system for the existing chemicals for the check of their safety, and in order to consider as the system that can judge safety, without examining, more advanced prediction accuracy is needed. Furthermore, it is necessary to clarify a scope, especially the domain of a substance with high prediction ratio. In this report, the problem in the case of determining the priority of directions or an examination required substance as test substitution data of a prediction result was considered.

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CAST/CNMR is the first system that solved the critical problem of the accurate distinction of differences and similarities in stereochemical structures around a specific carbon and achieved accurate and practical prediction of ¹³C-NMR chemical shift values. This paper describes about improvement of the accuracy with effective consideration of ring structures, which generally have influences on ¹³C-NMR chemical shift values. A new CAST code for representation of ring information is defined, which code has information on the size and the number of ring structures where the corresponding atom belongs. The CAST ring codes for atoms are represented with the same linear notation as the conformational and configurational CAST. The CAST ring notation is added to a structure-NMR spectral database of CAST/CNMR for taking the ring information into account for prediction. The accuracy is successfully improved with applications of the CAST/CNMR system to some natural organic compounds and their synthetic intermediates. Some applications to complicated polyether natural products including maitotoxin, monensin, and brevetoxin-B are demonstrated.

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We have been constructing a program system, called Data Base for Transition State (TSDB), which fuses the computational chemistry and information chemistry. TSDB includes a library, the transition stat library (TSLB) which consists of the name of reactions, skeletone and product names, geometry of reactants, products and TS, and other information. The data base was intended to examine whether or not synthesis routes obtained from TOSP or AIPHOS are feasible. It was confirmed that the classification method of the previous TSDB does not work well when the number of TS data in TSLB becomes large. Therefore, TSDB was modified a little to accommodate and use well the large number of TS information in the present study. We developed a new data base system called Find_TSINFO. The system uses the ChemFinder to give the function of the structure searching to TSDB. A small program was written in order to transform all the information in TSLB to data for Find_TSINFO.

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CONFLEX developed as the original method of conformational space search can cover low-energy regions preferentially. If an organic compound system of more than hundred atoms is searched, overall conformational space can be exhausted promptly by applying the newest parallel-distributing technique. In the present study, in order to achieve sufficient conformation for proteinic functional analysis, an improved algorithm based on CONFLEX that covers wide range of conformational space has been developed. The algorithm can effectively enhance the conformational searching with flexibly connect to the conformational databases of the peptide fragments where conformational search was completed beforehand.

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A novel fast docking program, the Ph4Dock (Pharmacophore Dock) has been developed. Ph4Dock is the first program that bridges docking study and pharmacophore based drug design. We have developed the automatic method to generate reasonable pharmacophore models for active sites within the receptor. Searching multi-conformation database of the ligand with automatically generated pharmacophore models, we could obtain reasonable initial guess structures of the ligand-receptor complex. Since ligand features such as hydrogen bond acceptors, donors and hydrophobes were aligned within the receptor at reasonable position from the beginning, rigorous full-atomistic optimization converged in short time. We validated this program with a biotin binding protein (2RTD.D). Although five pockets of reasonable size were detected by geometrical method in this receptor, Ph4Dock has successfully generated 10 lowest energy conformations in the single site in 157 sec. on 2.8GHz Pentium4 PC. The ligand geometry of the lowest energy complex is in excellent agreement with experimental binding mode with 0.36 angstrom root-mean-square.

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CYP3A4 catalyzes 10,11-epoxidation to carbamazepine (CBZ), anti-convulsant drug. This is only one CBZ metabolic route by CYP3A4. However, potential energy of CBZ 10,11-epoxide is about 30 kcal/mol higher than that of hydroxy CBZ. To elucidate the reason why CYP3A4 produces epoxide only in CBZ metabolism, a mechanism of CBZ epoxidation by CYP3A4 was investigated by using theoretical calculations. It was found that the active site of CYP3A4 had geometry to catalyze epoxidation to CBZ and that CBZ 10,11-epoxidation was two-steps reaction proceeding in doublet spin state. The activation energy of the rate-determining step was 13.8 kcal/mol and this reaction can occur in vivo. If hydroxylation mechanism of CBZ by CYP3A4 occurs, the activation energy of the first step reaction is higher than that of the rate-determining step of epoxidation of CBZ by CYP3A4. It is considered that the result explains the reason why 10,11-epoxidation of CBZ is only one CBZ metabolic route by CYP3A4.

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We have been developing "ab initio" computational methods for analyzing the electronic states, structures and dynamics of DNA. On the bases of computational methods such as fragment molecular orbital method, ab initio and classical molecular dynamic methods, and charge equilibration method, we are performing theoretical analyses mainly focusing on the following two issues. First, we are analyzing the mechanism of transcriptional regulation and the associated specific molecular recognition in the complex of DNA and regulatory proteins. Second, we are elucidating the electron transfer and transport in DNA, which are attracting considerable attention in the fields of radiation biology and nanotechnology applications.

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Proteins are huge molecules connected with a lot of amino acids, and about 1/3 amount of them contain metal ion. In order to clarify various reactions in proteins by quantum chemistry, our group has developed the density functional method program ProteinDF. ProteinDF can treat the whole protein as a molecule and calculate the all-electron taking in the electron correlation effect. Now, in the RR2002 project, we are studying the functions required for protein research, and are developing the protein quantum chemical calculation system based on ProteinDF. The system consists of 5 sub-systems: (1) integrated GUI, (2) automatic simulation, (3) ab initio molecular dynamics and geometry optimization, (4) module for supercomputer and (5) protein wavefunction database. In this study, we introduce our system with a few concrete calculations.

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Our study is to develop a molecular simulation system that can predict the unknown structures of various compounds. As the first step, we have set up a precise crystal force field based on the Cambridge Structure Database (CSD). Since the modeling of force field including CH-π interaction was built previously, in this work, we have extended the current crystal force field with taking into account various hydrogen bonding interactions between CH groups, OH groups, NH groups to O,N atoms, respectively. Intermolecular potential functions are represented by the combination between the non-bonded interactions as buffered-14-7 function and hydrogen bond interactions as Modified Lippincot-Schroder (MLS) function. Parameters of buffered-14-7 functions are determined same as the MMFF94 optimal parameters, and parameters of MLS function are optimized by a parameter-optimization program (KGA). The crystal structures are optimized with the newly determined parameters of MLS intermolecular potential by nano-crystal structure optimization program (KESSHOU). Therefore, it's confirmed in this study that reasonably good reproducibility of the optimized crystal structures has been achieved.

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The conformations of a phenyl ring situated in an axial position on 9-phenylbicyclo[3.2.2]nona-3,6-dien-2-one (4) and 9-methyl-9-phenylbicyclo[3.2.2]nona-3,6-dien- 2-one (5) were determined using a series of quantum chemical techniques, that is, semi-empirical MO, ab initio RHF, MP2 and DFT. The theoretical investigations suggested in chorus that, in accord with the conclusion we have previously drawn from 1H-NMR chemical shifts, the aromatic rings of the two compounds were oriented quite differently each other. This results were in contrast to the case of the phenylcyclohexane derivatives early reported by Allinger's group, where the phenyl ring in an axial position had the same perpendicular conformation due to syn-axial hydrogens repulsions, reflecting delicate differences in the magnitude of the intramolecular steric repulsions between the two cases. There might exist other key factors to influence the conformation of the phenyl ring of 4 and 5, i.e., so-called intra CH/π interactions. To elucidate the effects, we accomplished further calculations of model compound 10 and 11 whose double bond in question are reduced, leading to the exclusion of CH/π interaction.

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Ethylene glycol(EG) has two hydroxyl(OH) groups and can make intramolecular hydrogen bond(s), forming various conformers. In this study, we calculated the geometries of local minimum and transition state conformers using the HF/6-31G* and MP2/6-31G* levels of theory. The potential energy maps were made by single point calculations. The distribution of EG conformers at some temperature was obtained by means of ab initio MD calculations starting from two major conformers(tG+g-,tTt) using HF/6-31G*. The ab initio MD method performs ab initio MO calculations at each MD step. In the trajectory at 300K, the OCCO conformational isomerizations have not been observed. At 500K, EG changed its conformation in high energy region, and the OCCO conformational isomerizatons were observed several times. The OCCO conformational isomerizations occurred along the low energy area in potential energy maps at most of the times, while processes of isomerizations were observed via high energy conformations. The difficulty of the OCCO conformational isomerization is due to the high rotational barriers(about 5.4kcal/mol). In addition to those barriers, it is probable that the conformation and the direction of the movement of OH groups are important toward the OCCO conformational isomerizations.

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In order to elucidate the possibility of hydrogen transfer in the cyclic conjugated hydrogen-bonding system of malonaldehyde enols (the n-meric cyclamers of malonaldehyde, CMAn with n=3-10) DFT calculations were performed using B3LYP functionals with the 6-31G** basis sets. Two stable geometries with forms I and II about the hydrogen bonds in the cyclamers are defined as "[syn-anti]anti" and "[anti-syn]anti," respectively, on the basis of the CC-OH and CC=O...H configurations and the CO...OC conformation. Planar stable structures were obtained only for form I of CMA5 and CMA6. Bowl, chair, boat, and crown structures were found as nonplanar stable ones for the rest forms of CMA3-8. The energy differences between the two forms are very small for the chair and boat structures of CMA8. The barrier heights for the proton transfer are also very small for both the forms of CMA8. The values for the barrier heights reduce to 0.3-4 kcal/mol with the zero-point energy correction. The proton transfer for CMAn should exist for the chair and boat structures of CMA8 even in the solid state.

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The novel ZINDO method with a novel two-center electron repulsion integral, "new-gamma" were developed for the accurate calculation of the excitation energies of organic compounds. The values of spectrochemical softness parameter k of the new-gamma were evaluated from the absolute hardness (eta). The regression expression to evaluate the parameter k was determined to be "k = 6.97 / eta - 0.06" from the k0 and eta values of 6 acenes. The excitation energies of the 20 polycyclic aromatic hydrocarbons calculated by the novel method reproduced the observed values more accurately than those calculated by the general ZINDO method.

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We have been studying phenanthroline derivatives from the experimental and theoretical points of view. Recently, one of the authors (S. O.) reported that a new phenanthroline derivative featuring high selectivity for the lithium cation complexation as carriers was synthesized. The simplicity of this carrier 1 itself and highly efficient separation of LiCl from the mixture including various alkali metal chlorides would meet the practical uses. Since this molecule has the cavity ringed by oxygen and nitrogen atoms as a coordination site, this complexation to the lithium cation is new type of coordination. Calculations using ab initio restricted Hartree-Fock molecular orbital (RHF MO) theory with the 3-21G and 6-31G* basis sets are reported for phenanthroline derivatives as well as its lithium complexes. Force constant matrices were calculated at stationary points in order to identify them as minima. The optimized geometries are consistent with the structural formula expected from the experiment. Stoichiometry of the complex, complexation energies, and frontier orbitals are discussed.

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Elemental mercury and inorganic/organic mercury-containing compounds cause toxic effects in a number of systems and organs, depending on the chemical form of 2mercury. the methylation of Hg(II) by Methylcobalamin is particular of interest since it may represent one pathway, by which highly toxic methylmercury derivatives are formed in the environment. However, the mechanism for the observed reduction of inorganic mercury(II) in solution remains still unknown. We have examined the structures of inorganic and organic mercury with the B3LYP density functional method, and found that linear coordination of mercury is favored. Frontier molecular orbitals of (CH3)2Hg, (CH3)HgCl and HgCl2 for various C-Hg-C, C-Hg-Cl and Cl-Hg-Cl angles are investigated. The methylation mechanism of inorganic mercury by methylcobalamin is currently in progress.

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Intermolecular interactions play a significant role in the field of physics, chemistry and biology. The study of intermolecular interactions is a useful step toward gaining a basic understanding of the dynamic behaviour of molecules in various environments. Especially, interactions of the ammonia (NH3) molecule with other molecules provide valuable information on protein-protein interactions or protein-solvent interactions in biological systems. Today's ab initio methodologies are very powerful tool to investigate intermolecular interactions. However, the intermolecular interactions in trimers have been investigated less frequently than in dimers. From this point of view, high-level ab initio calculations [MP2] using correlation consistent basis sets of Dunning [aug-cc-pVTZ] were carried out to study the structures and stability of He2/NH3 and Ar2/NH3 Van der Waals trimers and to clarify the nature of three-body interactions. For the calculation of interaction energies, the basis set superposition errors (BSSE) were estimated by counterpoise method. The most stable structures have been obtained. For the optimized structures, Ar-Ar interaction in Ar2/NH3 is almost as strong as in Ar2 dimer. However, He-He interaction in He2/NH3 is considerably weaker than in He2 dimer.

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In an attempt to estimate the strain energy of three-, four-, and five-memebered cyclosilanes substituted with a heteroatom or group, [R2Si]nX; n=2,3 and 4; X=CH2, NCH3, O, SiH2, PCH3 and S; R=H and i-Pr, we have performed high level ab initio molecular orbital calculations, some involving the ONIOM method. It was found that the bond distances, bond angles and lone-pair electrons play important role for the strain energy of cyclosilane substituted with a heteroatom or group. The cyclosilanes substituted with the third-row elements tend to have smaller strain energy compared to the second-row analogues. On the other hand, upon substitution by bulky groups such as i-Pr on silicon atoms, the ring expands and the strain energy is released but at the same time the existence of the bulky substituents brings about the steric repulsion between lone-pair electrons on the heteroatom or group which leads to increase of the strain energy.

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Comprehensive study for cyclosilanes substituted with a hetero atom(group) had been less than for unsubstituted cyclosilanes. We have not still known the properties in detail. However, as the release of the experimental data for the syntheses, structures, and photoreaction have performed recently. Therefore, we have carried out high level ab initio molecular orbital calculation to explore the properties, especially for the reactions. In the present study, we interpret the mechanism of the ring-opening reaction for X(SiH2)3,X;CH2,NH,O, and SiH2. The geometries of all molecules have been fully optimized at CASSCF(8,8) or (12,12) level with the 6-31G(d). Furthermore, the single point energy calculations have been carried out at MRMP2 level on the CASSCF geometries. The vibrational frequency calculation have been performed at the CASSCF level. We discuss the relation between the energy barrier of ring-opening reactions in the ground state and ring strain energy. For O(SiH2)3. It is found that the energy barrier for the ring-opening estimated at the CASSCF(12,12) (with lone-pair electrons) is higher than that at the CASSCF(8,8) level. This result suggests that the lone-pair electrons tend to make the ring structure more rigid compared to the case without them.

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Oligonucleotides containing phenylsulfoxide derivative of 2-amino-vinylpurine nucleoside analogue are activated within duplex to form cross-link toward cytidine selectively at the target site. We have already studied the mechanism of the reaction by using the model system and our theoretical calculations at the B3LYP/6-31G* level of theory. These studies suggested that the geometry of the DNA duplex or the electronic effect of the base pair of 2-amino-vinylpurine is strongly related to why the cross-link reaction occurs in the duplex. In the present study, we tried to find the best method which express correctly the steric effect of the duplex for activation of the phenylsulfoxide fragment. The ONIOM(B3LYP/ 6-31G*:UFF) level of theory was first used for optimizing the reactants including three base pairs. A TS geometry was obtained at ONIOM(B3LYP/6-31G*:AM1) level of theory. The geometries of the active fragments in both structures were calculated to be very similar to that of the TS structure in the small model system. According to the error in executing other geometry optimizations by use of the ONIOM method, the B3LYP method including the 6-31G* basis sets in the reactive fragment and the STO-3G basis sets in the rest of the molecules were applied to optimize the model reactants with three base pairs.

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SM3 antibody is bound specifically to MUC1 which appears on the membrane of the breast cancer cell. It has a potential as a therapeutic and diagnostic tool. But its binding time is too short to be used as medicine at present. Accordingly, it will be keen important to design a modified SM3 antibody that has the longer binding time and the higher affinity. For the purpose of improving the affinity of the antibody, we executed molecular dynamics simulation using the calculation program AMBER7. From the computation for sixteen antigen-antibody complex, we revealed that we can calculate accurate bonding affinity from evaluation synthetically B-Factor dimension and enthalpy obtained from Jayaram's GB method. Also we investigated existent SM3 antibody-MUC1 binding pattern.

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Mannose-binding protein (MBP) plays a crucial role in the human innate immunity system through the recognition of mannose. Binding properties of MBP to six monosaccharides are discussed based on ab initio molecular orbital calculations for three types of cluster models constructed using 3D structure. The calculated binding energies are well consistent with the biochemical experimental results. Electrostatic potential iso-surfaces at the binding site suggest that sugar residues are selected by electrostatic force dominantly. A vacant frontier orbital localized at the binding site of MBP and in-phase frontier orbitals of four binding monosaccharides are found. Moreover, HOMO of Man is affected by MBP through complexation. The change of net atomic charges and internuclear distances upon complexation suggest the formation of hydrogen bond networks. We conclude that MBP recognizes sugar residues in the two stages; (1) electrostatic potentials are essential to sugar preference by MBP, (2) in addition to the electrostatic potentials, orbital interactions and hydrogen bonds play an important role in the complexation.

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A novel docking and database-searching program, Ph4Dock(Pharmacophore Dock, cf., J14), is developed and tested with X-ray crystal structures of ligand-receptor complexes. Currently available docking/screening programs starts docking calculation with random initial structures of ligands in the limited region around the designated binding site. Ph4Dock not only utilizes the shape of the candidate ligand-binding site, or pocket, but further restricts the features of small compounds. It first searches the pockets on receptors and utilizes all available chemical features on the receptor surface at the pockets to build pharmacophore queries representing the preferred features of ligands: the chemical features used for the Pharmacophore are hydrogen-bond donor or anion, hydrogen-bond acceptor or cation, and hydrophobe or aromatics. With this unique feature, ligand-binding sites are easily distinguished from other pockets and, inversely, possible ligands can be rapidly screened. The screened hits are then optimized from the already preferentially aligned structures in relatively short time compared with traditional docking/screening programs.

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Protein Data Bank (PDB) is the common data source of protein geometries. However, the most structures are determined by X-ray diffraction (about 85 percents) which causes the lack of hydrogen atoms positions. In addition, distorted and/or indistinct geometries are often observed in PDB data. It is necessary to check the validity to PDB data for simulations on proteins, in particular molecular orbital (MO) calculations. Since protein has huge and complicated structure, automatic support is indispensable. In this study, we developed a new molecular modeling program for PDB data to support simulations on proteins. Our program has functions of hydrogen addition, checking the structural validity, amino acid substitution (point mutation) and chemical modification to PDB. Referring the PDB hetero group dictionary, the modeling such as hydrogen addition is easily achieved to proteins containing hetero groups which have a large variety of bonding patterns. The program was coded by the object oriented language C++ and developed as standalone library.

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The prototype of a structure optimization program for large-scale proteins was developed, in which molecular orbital method program ProteinDF based on density functional method is used. This structure optimization program is subsystem of the quantum chemistry calculation system. In this program, energy gradient calculation uses the ProteinDF program and optimization calculation uses the conjugate gradient method. As an example of the structure optimization using this program, we performed to some peptides of Cytochrome c.

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We have developed a density functional program, ProteinDF, for all-electron calculations on proteins. Those calculations inevitably require very good initial guesses, and a new self-consistent field (SCF) convergence method was proposed by using quasi-canonical localized orbital (QCLO). QCLO is localized in a certain region of molecule, but it is also the canonical molecular orbital (MO) of the region. Convergence of all-electron calculation on proteins is achieved by the following process. In the first step, we made calculations on all single amino acids. In the second step, tri-peptides of 1-3, 2-4, ··· and (N-2)-N residues were calculated. In the third step, peptides composed from several residues were computed from the initial MO combining QCLO of the middle residues of tri-peptides. Iterating this type of process, finally we can obtain canonical MOs of proteins. In this study, we parallelized this method to apply large scale calculations. Since both the number and size of peptides changes a lot in each step, three kinds of parallelization algorithms were adopted to keep the high efficiency. In addition, we introduced the hierarchical parallelization to govern those algorithms, where processors are divided into some groups and each group individually carries out the own parallel job. The number of groups and processors in each group are rearranged by the number and size of peptides in each step.

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In order to manipulate information on organic reactions, we have proposed ITS (Imaginary Transition Structures) and employed ITS connection tablers as internal representations.Such ITS connection tables have been manually constructed and inputted into a computer by using a keyboard until now.In order to perform computer processing more smoothly, it is necessary to develop a more efficient method of inputting the ITS connection tables.In this research, a chemical reaction scheme is written by ChemDraw and the resulting MDL molfile is employed as original data.It is converted into an ITS connection table by a newly developed device for this purpose.

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We have been constructing a program system, called Data Base for Transition State (TSDB), which fuses the computational chemistry and information chemistry. TSDB includes a library, the transition stat library (TSLB) which consists of the name of reactions, skeletone names, product names, geometry of reactants, products and TS, and other informations. The data base was intended to examine whether or not synthesis routes obtained from TOSP or AIPHOS, the synthesis route design system developed by Funatsu et al, are feasible. In the present study, we developed a new data base system called Find_TSINFO running on Windows2000. The system uses the ChemFinder to give the function of the structure searching to TSDB. The TS information such as coordinates, heat of formations and equations of chemical reactions are displayed in the window. Buttons are included in order to execute Chem3D from the data base. A small program was written in order to transform all the information in TSLB to data for Find_TSINFO. Demonstartion for how Find_TSINFO works will be shown.

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A database that accumulates information on large amount of organic reactions is very important to R & D of organic chemistry. Although there exist several commercial databases, there remain problems in manipulating the information. We have found that reaction strings abstracted from ITS (Imaginary Transition Structures) work as search keys in organic reaction databases. We will describe a program for abstracting such reaction strings, which are applied to carry out reaction property retrieving and coding.

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An NMR spectral database for organic natural products "CH-NMR-NP" has started to build since April 2002 by compiling the NMR spectral data of the natural products from the literatures (Chem. Pharm. Bull., J. Antibiotics, Tetrahedron, Tetrahedron Letts., Magn. Reson. Chem., J. Nat. Prod., J. Org. Chem., Eur. J. Org. Chem. and others) issued in 2002. The number of the data collected from the Journals in 2002 was about 1150 in the CH-NMR-NP. The accumulation of the data is continuing for the Journals issued in 2003 and the total number of the compiled data is 1,600 at the end of September 2003. The serach and disply system is working on a web system.(noy yet opened to public).

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Integrated Spectral Database System for Organic Compounds (SDBS) has a long history of development since 1981. The SDBS system is opened to public through the Internet free of charge since April 1997. By the end of August 2003 the total number of access exceeded 57 million. The large number of accesses and the remarks from all over the world has proved the importance and necessity of SDBS. In order to keep the activity of SDBS with keeping the quality of the database, it is extremely important to maintain simple and easy data management in adding and replacing data. Exporting the data to the Internet system must be handled simple and easy, as well. We upsized our input tool system with MySQL as a DBMS; furthermore, we added a data export system for opening the data to the Internet. With the upgrade, we opened MS, NMR and IR data in addition to the compound information to the Internet.

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In this study, the management of the chemical substance information that used XML technology was examined. The chemical substance information other than the structural formula was able to be made the XML document easily. And the structural formula can be made the XML document, after transforming into the MDL mol format. The schema for CML(Chemical Markup Language) is used as the definition of XML document in this study. The XML document that was generated is having it without lacking the original information, and it is handled to a simple target. Also, the XML document is processed by the open source or free softwares of the established that can handle it. The chemical substance information inside the XML document is generated as a new XML document, whether or not it is displayed to the browser, after it was processed. Because it is possible to obtain those softwares easily, anyone is able to refer to the XML document including chemical substance information.

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We have developed three different types of organic synthesis design systems (AIPHOS, KOSP, TOSP). On the other hand, in order to evaluate the synthetic pathway proposed by the design synthesis, a system which predicts reaction by-product has been developed. This system can evaluate synthetic pathway with attention to the safety and reaction condition for by-product. Prediction of reaction by-product is very important in design of organic synthesis. However, such a system had not been developed in spite of its importance. Then, we developed the Client/Server (C/S) system which unifiesthree organic synthesis design systems and the prediction system of reaction by-product. This C/S system can use three organic synthesis design systems and the prediction system of reaction by-product with common interface. The server of this unified system runs on Linux or IRIX.And the corresponding client runs on Microsoft Windows. This C/S system can evaluate synthetic pathway by prediction of reaction by-product simultaneously with searching synthetic pathway.

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Translation of IUPAC systematic organic chemical nomenclature into chemical structure has been applied by computer system CHEMNAME to fused and bridged fused ring systems on the basis of IUPAC recommendations 1998. Letter locants of the parent component in fusion descriptors are converted to the numerical numberings going from the atom with locant 1 through sequence of bond that belongs to one ring. Omitted locants at the fusion atoms are recovered in the same way. Recovery is also supported when all locants on a component are omitted e.g. benzo[7]annulene, pyrazino[g]quinoxaline. Numbering proceeds as follows. Duplicated atoms after fusion are compressed to give a connection table of the fused ring system. Ring components are extracted and numbered. Whole sets of rings arranged in a straight line are collected. A ring set is expressed by numberings of rings, of fusion atoms on upper and down sides of the straight ring line. A linear set with maximum number N of rings (J=1 to N) are arranged on axis y=0, each ring being at x=2J-N-1. X,Y-arrangement of each ring is obtained by crossing two linear ring sets at a common ring. Then the starting atom of numbering and clockwise direction around the system are obtained. The real locant set is selected by consideration of the preference rules. Numbering of bridge atoms are ruled in detail by the recommendations and the rules are applied to our system without difficulty.

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We have been developing a graphical user interface program, Molecular Information Communication System (MICS), to visualize the data (molecular structure, molecular orbital, vibration, and chemical reaction) calculated by the programs of Gaussian and GAMESS. This system includes not only the function of visualization, but also the function of molecular modeling to make and edit molecule. The function of molecular modeling provides to design molecule as coordinate of Z-matrix or as moving of mouse, and it is possible to preserve it as input file. Also, this system can be used on multi platform. Because we used the programming language of Java and OpenGL, and confirmed to be moving on Windows2000, Me, 98, MacOSX, and Linux (RedHat).

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133,251 terms extracted from literature in biochemistry and biology were processed to automatically extract semantic relationships. Extracted terms represent biochemical and biological concepts, and the network generated by linking concepts according to semantic relationships represents the biochemical and biological knowledge. The conceptual network has double scale-free property, and two hierarchical levels of clustering. Scale-free property indicates that the evolution of the conceptual network is not a random process. Analysis suggest that a new concept is introduced to the conceptual network with single relationship, and progressively conncects to a group of concepts with 15-20 relationships. This number is the threshold of clustering hierarchy. Concepts jumping this threshold seem to become important and/or general concepts.

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It is obvious that the various properties of an organic compound are closely related to the structure of it. In order to find out the existing relationships, various methods have been devised and tested. There are several graph theory based methods among them. We have developed a method named COMPASS (COMmon geometric PAttern Search System) for assessing the similarity of two molecules with three-dimensional Euclidean distances between corresponding atoms. In the present study, we have developed a new system based on the COMPASS that will find common three-dimensional substructures comprehensively among molecules with similar activity. This system can enumerate all the fragments which contain more than the specified number of atoms and search for those fragments which appear at specified frequency or more in the given set of molecules.

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Because there is an enormous number of a conformation, it is difficult to estimate the pharmacophore and to do docking-study with the receptor using the 3D structure information that acquired from search of drug molecules' all stable conformation. So, there is the need to narrow down the comparison of conformation. In this research, we visualize the property-vector of pharmaceutical's 3D stable conformation using the Self-Organization Map(SOM: Kohonen map) that is a kind of the neural network. We have developed SOM data mining system. It specializes specialist's knowledge and analysis can be performed interactively. This time, we tried the analysis to three kinds of HIV virus protease Inhibitors.

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With advanced computer technology, the importance of data mining is growing to extract useful information from huge amount of numerical data. Also in the domain of chemistry, many experimental data are being accumulated by combinatorial chemistry and high throughput screening (HTS) and so on. In order to find benefit information from these data, a lot of methodologies of chemometrics have been developed. Since usually these numerical data are represented as multi-dimensional array, traditional statistical software cannot handle these data directly. In this study, we developed the data modeling software, which handles multi-dimensional array effectively. By using this software we come to be able to analyze of multi-dimensional data. It is possible to understand the structure of multi-dimensional data by using graphical representation such as bar graph, line graph and so on. And as data modeling method, Multi-way PLS (partial least squares) and Kohonen neural network are available in order to analyze multi- dimensional data.

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