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ABSTRACT: We develop an inter-fragment interaction energy (IFIE) analysis based on the three- and four-body corrected fragment molecular orbital (FMO3 and FMO4) method to evaluate the interactions of functional group units in structure-based drug design context. The novel subdividing fragmentation method for a ligand (in units of their functional groups) and amino acid residues (in units of their main and side chains) enables us to understand the ligand-binding mechanism in more detail without sacrificing chemical accuracy of the total energy and IFIEs by using the FMO4 method. We perform FMO4 calculations with the second order Møller-Plesset perturbation theory for an estrogen receptor (ER) and the 17β-estradiol (EST) complex using the proposed fragmentation method and assess the interaction for each ligand-binding site by the FMO4-IFIE analysis. When the steroidal EST is divided into two functional units including "A ring" and "D ring", respectively, the FMO4-IFIE analysis reveals their binding affinity with surrounding fragments of the amino acid residues; the "A ring" of EST has polarization interaction with the main chain of Thr347 and two hydrogen bonds with the side chains of Glu353 and Arg394; the "D ring" of EST has a hydrogen bond with the side chain of His524. In particular, the CH/π interactions of the "A ring" of EST with the side chains of Leu387 and Phe404 are easily identified in cooperation with the CHPI program. The FMO4-IFIE analysis using our novel subdividing fragmentation method, which provides higher resolution than the conventional IFIE analysis in units of ligand and each amino acid reside in the framework of two-body approximation, is a useful tool for revealing ligand-binding mechanism and would be applicable to rational drug design such as structure-based drug design and fragment-based drug design.
Journal of molecular graphics & modelling 02/2013; 41C:31-42. · 2.17 Impact Factor
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04/2012; , ISBN: 978-953-51-0443-8
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ABSTRACT: Updated version of National Institute of Health Sciences Computer Network System (NIHS-NET) is described. In order to reduce its electric power consumption, the main server system was newly built using the virtual machine technology. The service that each machine provided in the previous network system should be maintained as much as possible. Thus, the individual server was constructed for each service, because a virtual server often show decrement in its performance as compared with a physical server. As a result, though the number of virtual servers was increased and the network communication became complicated among the servers, the conventional service was able to be maintained, and security level was able to be rather improved, along with saving electrical powers. The updated NIHS-NET bears multiple security countermeasures. To maximal use of these measures, awareness for the network security by all users is expected.
Kokuritsu Iyakuhin Shokuhin Eisei Kenkyūjo hōkoku = Bulletin of National Institute of Health Sciences 01/2012;
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ABSTRACT: Ab initio electronic-state calculations for influenza virus hemagglutinin (HA) trimer complexed with Fab antibody were performed on the basis of the fragment molecular orbital (FMO) method at the second and third-order Møller-Plesset (MP2 and MP3) perturbation levels. For the protein complex containing 2351 residues and 36,160 atoms, the inter-fragment interaction energies (IFIEs) were evaluated to illustrate the effective interactions between all the pairs of amino acid residues. By analyzing the calculated data on the IFIEs, we first discussed the interactions and their fluctuations between multiple domains contained in the trimer complex. Next, by combining the IFIE data between the Fab antibody and each residue in the HA antigen with experimental data on the hemadsorption activity of HA mutants, we proposed a protocol to predict probable mutations in HA. The proposed protocol based on the FMO-MP2.5 calculation can explain the historical facts concerning the actual mutations after the emergence of A/Hong Kong/1/68 influenza virus with subtype H3N2, and thus provides a useful methodology to enumerate those residue sites likely to mutate in the future.
Journal of molecular graphics & modelling 07/2011; 30:110-9. · 2.17 Impact Factor
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ABSTRACT: The periodic boundary condition (PBC) is incorporated in the fragment molecular orbital (FMO) method to appropriately describe systems with aqueous solutions. We present benchmark calculations for (H2O)64 and show that this PBC-FMO method can eliminate artificial surface effects. An application to molecular dynamics simulation for liquid water is also shown, and calculated radial distribution functions are in reasonable agreement with those obtained from experiments. It is thus confirmed that the present PBC-FMO method is useful for ab initio simulations in aqueous solution.
Chemical Physics Letters 04/2011; 506(1-3):112-116. · 2.34 Impact Factor
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Chemistry 06/2010; 16(22):6430-3. · 5.93 Impact Factor
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ABSTRACT: The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a direct pharmacological target for drugs that enhance insulin sensitivity and are used clinically for the treatment of type II diabetes. Because the specificity of ligand recognition is lower for PPARgamma than for other nuclear receptors, PPARgamma can bind a larger variety of ligand types. In order to elucidate why the ligand recognition of PPARgamma is so flexible, we performed correlated fragment molecular orbital calculations for complexes of PPARgamma and each of two distinctive ligands, rosiglitazone and farglitazar. We found quite different patterns of ligand binding for these two ligands. The ligand-binding system of rosiglitazone, a drug in common clinical use, is based mainly on local electrostatic interactions around the thiazolidine ring, whereas both electrostatic interactions and van der Waals dispersion interactions with hydrophobic residues are required for the binding of farglitazar to PPARgamma. We suggest that the development of novel ligands will require adequately hydrophobic pharmacophores.
Bioorganic & medicinal chemistry letters 06/2010; 20(11):3344-7. · 2.65 Impact Factor
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ABSTRACT: We discuss the accuracy of fragmentation in fragment molecular orbital (FMO) calculations for the hydrated sodium ion. Two-body expansion shows a considerable error in total energy even if water molecules in the second hydration shell are included in the same fragment as the sodium ion. Inclusion of the three-body term significantly improves both the total energy and the charge distributions. We also illustrate the dependence of the net charge of sodium ion on solvent size and the interfacial property of water molecules. The present study will thus provide fundamental information about hydrated ion to facilitate further theoretical and experimental studies.
Chemical Physics Letters 08/2009; 478(4-6):295-300. · 2.34 Impact Factor
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ABSTRACT: Fragment molecular orbital (FMO) and FMO-MO (MOs of the FMO) calculations with three typical fragmentations were performed for DNA molecules with various lengths up to 40 base pairs (bps) to validate the accuracy of the total energy and the interfragment interaction energy (IFIE). The respective accuracies of the FMO energies are 5.8 × 10−5, 1.3 × 10−4, and 5.0 × 10−3 hartree/bp for large, medium, and small fragmentations with HF/STO-3G, all sufficiently satisfying chemical accuracy. Two iterative calculations of the FMO-MO methods gave sufficient accuracy as less than 6.6 × 10−5 hartree/bp even with small fragmentation. The IFIE validations showed that IFIE, even with small fragmentation, has sufficient accuracy for chemical analyses. Small fragmentation is useful for the interaction analysis, not only for the hydrogen bonding interaction of base pairs but also for the stacking interaction of bases. For analyses of DNA molecules, IFIE analysis with small fragmentation is expected to be a powerful tool. Some frontier MOs of the largest model DNA examined in this study were delocalized over multiple base pairs, which well reflected the conductivity of DNA by a coherent mechanism. Such delocalized MO cannot be obtained in terms of the usual FMO calculation. This is a typical demonstration of the advantages of the FMO-MO calculation. These fundamental data for validation of the total energy and IFIE are expected to promote FMO and FMO-MO applications to biosystems related to DNA molecules.
Journal of Computational and Theoretical Nanoscience 05/2009; 6(6):1328-1337. · 0.91 Impact Factor
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ABSTRACT: We have performed a quantum-chemical MP2/6-31G* calculation for the hemagglutinin (HA) antigen-antibody system of the H3N2 influenza virus with the fragment molecular orbital method, which provides one of the world's largest ab initio electron-correlated calculations for biomolecular systems. On the basis of the calculated interfragment interaction energies (IFIEs) representing the molecular interactions between the amino acid residues in the antigen-antibody complex, we have identified those residues in the antigenic region E of HA protein that are significantly recognized by the Fab fragment of antibody with strongly attractive interactions. Combining these IFIE results with those of hemadsorption experiments by which the mutation-prohibited sites are specified has enabled us to explain most of the historical mutation data (five of six residues), which would thus provide a promising method for predicting the HA residues that have a high probability of forthcoming mutation.
The Journal of Physical Chemistry B 05/2009; 113(15):4991-4. · 3.70 Impact Factor
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ABSTRACT: We have performed a series of fragment molecular orbital (FMO) calculations for a family of red fluorescent proteins, DsRed and mFruits. The electronic transition energies were evaluated by the method of configuration interaction singles with perturbative doubles [CIS(D)] including higher-order corrections. The calculated values were in good agreement with the corresponding experimental peak values of spectra. Additionally, the chromophore environment was systematically analyzed in terms of the interaction energies between the pigment moiety and neighboring residues. It was theoretically revealed that the electrostatic interactions play a dominant role in the DsRed chromophore, whereas the color tunings in mFruits are controlled in a more delicate fashion.
The Journal of Physical Chemistry B 02/2009; 113(4):1153-61. · 3.70 Impact Factor
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ABSTRACT: The ab initio fragment molecular orbital calculations were performed for the alpha-subtype of the human retinoid X receptor (hRXRalpha) complex with its natural ligand 9- cis retinoic acid (9cRA) to quantitatively specify the key residues with important roles for the ligand inducible information transmission of RXR. In the RXR-9cRA complex, the transactivation helix 12 (H12) adopts a canonical agonist conformation, which just corresponds to the transcriptional activation function 2 activating domain core (AF2C). Through the analyses of molecular interactions by the second-order Møller-Plesset perturbation (MP2) method, it was proved that Trp305 and Leu436 of the AF2C binding pocket would be important for the stabilization of the H12 canonical agonist conformation, and, at the same time, for the recognition of the 9cRA molecule. Besides, through the analyses of orbital interactions by the local MP2 (LMP2) method, it was found that Trp305 and Leu436 would recognize the 9cRA molecule especially at its C19 methyl group, which has been most notably targeted to modify for agonist and antagonist design. Moreover, on the basis of the relationships of molecular interactions, it was suggested that the interactions of Trp305 and Leu436 with AF2C residues would be significantly influenced by the interactions of Trp305 and Leu436 with 9cRA. Taken together, our findings quantitatively demonstrated that Trp305 and Leu436 would be the possible key residues for the information transmission in liganded RXR, accounting for their importance suggested by experiments. Altogether, these results substantiated that our approach is useful for the understanding of the detailed molecular mechanism underlying the transcriptional regulation of RXR and related nuclear receptors at the quantum mechanical level.
The Journal of Physical Chemistry B 09/2008; 112(38):12081-94. · 3.70 Impact Factor
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ABSTRACT: We applied the fragment molecular orbital (FMO) method, which enables total electronic calculations of large molecules at ab initio level, to the evaluation of binding affinities between the human progesterone receptor ligand-binding domain (PR LBD) and various steroidal ligands. The FMO calculations were performed on the entire structure of the PR LBD, which is composed of approximately 4,100 atoms. Our computational binding energies of PR LBD/ligand complexes agreed well with experimental binding affinities (r=0.909). Interaction energies between each ligand and specific amino acid residues were also obtained from the FMO calculations. The principal residues involved in the interactions with these ligands were Arg766 and Asn719, with some additional contribution by Gln725. The main factor determining differences in binding affinity of the various ligands was not interactions with particular residues, but with the binding-site residues closest to the ligand. The interfragment interaction energy analysis is proving to be a useful method for gaining detailed information on ligand binding.
Archiv für Experimentelle Pathologie und Pharmakologie 07/2008; 377(4-6):607-15. · 2.65 Impact Factor
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ABSTRACT: For the three complex crystal structures of HIV-1 aspartic protease (an enzyme of AIDS) with its inhibitor in the Protein Data Bank, molecular dynamics of the generalized Born surface area and the ab initio fragment molecular orbital of an ABINIT-MP calculation was performed to obtain the binding free energy, the molecular orbital energy, the interaction energy of residues with an inhibitor and the charge transfer at the active site. The inhibitors are five symmetric cyclic ureas, of which three were modelled, and an asymmetric dipeptide. The interaction energy of the inhibitor at the active sites of aspartic acid is as great as 50 kcal mol(-1), coinciding with a tetrahedral transition state. For the inhibitor with a higher affinity, charge was transferred to the inhibitor from the active site. The difference in symmetry of the inhibitor was not evident. Binding free energy corresponds to the experimental value of the binding constant, while molecular orbital energy does not always, which is considered to be an entropy effect.
Journal of Synchrotron Radiation 06/2008; 15(Pt 3):239-42. · 2.73 Impact Factor
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ABSTRACT: Fragment Molecular Orbital based-Molecular Dynamics (FMO-MD, Komeiji et al., Chem Phys Lett 2003, 372, 342) is an ab initio MD method suitable for large molecular systems. Here, FMO-MD was implemented to conduct full quantum simulations of chemical reactions in explicit solvation. Several FMO-MD simulations were performed for a sphere of water to find a suitable simulation protocol. It was found that annealing of the initial configuration by a classical MD brought the subsequent FMO-MD trajectory to faster stabilization, and also that use of bond constraint in the FMO-MD heating stage effectively reduced the computation time. Then, the blue moon ensemble method (Sprik and Ciccotti, J Chem Phys 1998, 109, 7737) was implemented and was tested by calculating free energy profiles of the Menschutkin reaction (H3N + CH3Cl --> +H3NCH3 + Cl-) in the presence and absence of the solvent water via FMO-MD. The obtained free energy profiles were consistent with the Hammond postulate in that stabilization of the product by the solvent, namely hydration of Cl-, shifted the transition state to the reactant-side. Based on these FMO-MD results, plans for further improvement of the method are discussed.
Journal of Computational Chemistry 05/2008; 30(1):40-50. · 4.58 Impact Factor
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Journal of the American Chemical Society 03/2008; 130(8):2396-7. · 9.91 Impact Factor
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ABSTRACT: The ab initio fragment molecular orbital (FMO) calculations were performed for retinoid X receptor (RXR) complexes with its ligand 9-cis retinoic acid (9cRA) and steroid receptor coactivator-1 (SRC1) to examine the influence of mutations in transcriptional activation function 2 activating domain core (AF2C) of RXR on molecular interactions between 9cRA liganded RXR and SRC1 coactivator. The RXR-SRC1 interactions in three types of RXR-9cRA-SRC1 complexes, namely, a wild type (WT), a mutant whose Glu453 of AF2C was substituted by Lys (E453K), and another mutant whose Glu456 of AF2C was substituted by Lys (E456K), were compared. Through the comparison of WT, E453K, and E456K, possible causes for a marked decrease in the transcriptional activity of RXR by the mutation of Glu453, which is known as a highly conserved charged residue of AF2C, were discussed. It was quantitatively demonstrated that the strength of the RXR-SRC1 interaction correlates with the degree of the transcriptional activation (WT > E456K > E453K). In E453K, the RXR-SRC1 interaction was substantially reduced by the AF2C-SRC1 repulsive interaction, and the charge transfer (CT) from RXR to SRC1 was also inhibited by the decreased electron donation from AF2C to SRC1. Our findings suggest that the inhibitions of the local RXR-SRC1 interaction via AF2C and of the local CT from RXR to SRC1 via AF2C would be the possible causes for the marked decrease in the transcriptional activity of RXR.
The Journal of Physical Chemistry A 03/2008; 112(10):1986-98. · 2.95 Impact Factor
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ABSTRACT: We have developed a fragment interaction analysis based on local MP2 (FILM) in the context of the fragment molecular orbital
(FMO) scheme. The primary purpose of this work is to provide a tool for analyzing inter-fragment interaction associated with
dispersion interactions in a large molecule such as protein and DNA. Our implementation of local MP2 (LMP2) is based on the
algorithm developed by Pulay and Werner. A potential of FILM was demonstrated using the human immunodeficiency virus type
1 protease (HIV-1 PR) complexed with lopinavir (LPV). The total energy, binding affinity, and inter-fragment interaction energy
(IFIE) by the FMO method using LMP2 were compared with those obtained by canonical MP2 and the site-specific information in
dispersion interaction was obtained. It turned out that the FILM is a useful tool for analyzing the dispersion interaction
between an amino acid residue and a specific site of a ligand.
Theoretical Chemistry Accounts 11/2007; 118(5):937-945. · 2.16 Impact Factor
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ABSTRACT: A visualization method for inter-fragment interaction energies (IFIEs) of biopolymers is presented on the basis of the fragment molecular orbital (FMO) method. The IFIEs appropriately illustrate the information about the interaction energies between the fragments consisting of amino acids, nucleotides and other molecules. The IFIEs are usually analyzed in a matrix form called an IFIE matrix. Analyzing the IFIE matrix, we detect important fragments for the function of biomolecular systems and quantify the strength of interaction energies based on quantum chemistry, including the effects of charge transfer, electronic polarization and dispersion force. In this study, by analyzing a protein-DNA complex, we report a visual representation of the IFIE matrix, a so-called IFIE map. We comprehensively examine what information the IFIE map contains concerning structures and stabilities of the protein-DNA complex.
Biophysical Chemistry 11/2007; 130(1-2):1-9. · 2.20 Impact Factor
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ABSTRACT: Molecular orbital calculations of the complex between DNA-ERE (estrogen response element) and ER (estrogen receptor)-DBD (DNA-binding domain) were performed using the fragment molecular orbital (FMO) method, which enables large-scale MO (molecular orbital) calculations by reducing the computational cost and by significantly increasing efficiency for parallel computation. Such a large system, which contains 3354 atoms, is impractical via conventional MO methods due to the immense computational cost. Details of the interaction between DNA-ERE and ER-DBD were revealed in this study as follows by using the FMO calculations to analyze the interfragment interaction energies (IFIEs) and the electrostatic potentials (ESPs). An area with a high positive ESP is identified on the DNA-binding side of ER-DBD and is the main driving force behind access to the DNA. The position of the ER-DBD monomer can be fixed on a phosphate group of DNA-ERE by the strong electrostatic interactions, whereas the rotation cannot be fixed. In contrast, both the position and rotation of the ER-DBD dimer can be fixed and can therefore form the stable (ER-DBD)2...DNA-ERE complex. Dimerization of the ER-DBD monomers, each of which have a charge of +5 , is mainly due to large attractive interaction energies of the second Zn fragments. The base pairs in the consensus sequence of DNA-ERE interact only with the recognition helix located in the major groove due to the large shielding effect of the phosphate groups of DNA. The recognition helix has weaker interactions with the base pairs than the electrostatic interactions with the phosphate groups. Thus, the DNA-binding machinery of the ER-DBD dimer, which can secure the recognition helix in the major groove of DNA, is crucial for interactions between the recognition helix and base pairs.
The Journal of Physical Chemistry B 09/2007; 111(32):9621-7. · 3.70 Impact Factor
