Biomedical subjects

Kazuo Kitaura

Publications and source records attributed to Kazuo Kitaura.

15 recordsLinked to original sources

PubMed2007

Pair interaction energy decomposition analysis.

The energy decomposition analysis (EDA) by Kitaura and Morokuma was redeveloped in the framework of the fragment molecular orbital method (FMO). The proposed pair interaction energy decomposition analysis (PIEDA) can treat large molecular clusters and the systems in which fragments are connected by covalent bonds, such as proteins. The interaction energy in PIEDA is divided into the same contributions as in EDA: the electrostatic, exchange-repulsion, and charge transfer energies, to which the correlation (dispersion) term was added. The careful comparison to the ab initio EDA interaction energies for water clusters with 2-16 molecules revealed that PIEDA has the error of at most 1.2 kcal/mol (or about 1%). The analysis was applied to (H2O)1024, the alpha helix, beta turn, and beta strand of polyalanine (ALA)10, as well as to the synthetic protein (PDB code 1L2Y) with 20 residues. The comparative aspects of the polypeptide isomer stability are discussed in detail.

Journal Article↗

PubMed2006

Binding affinity prediction of non-peptide inhibitors of HIV-1 protease using COMBINE model introduced from peptide inhibitors.

Comparative binding energy (COMBINE) analysis method is one of the QSAR techniques for the prediction of biological activities of inhibitors based on interaction energies between ligands and proteins decomposed into each amino acid residue. We supposed that the predictive ability of the COMBINE method does not depend essentially on the molecular frameworks of ligands. To verify this idea, we performed the COMBINE analysis of non-peptide inhibitors of HIV-1 protease (HIVp), where the prediction model was constructed using inhibitors with a peptide scaffold as a training set. The predictive performance of the AMBER and CHARMm force fields was very high and at the same level (q(2)=0.75, 0.67, SDEP(cv)=0.76, 0.89, and SDEP(ex)=0.92, 0.66, respectively). The high predictive ability of the COMBINE method for the distinct scaffold compounds is due to the informative description of the interaction energies for compounds that are located at the binding site. This result suggests that COMBINE analysis may be applied not only to the lead optimization stage but also to the lead evolution stages.

Amino Acids↗

PubMed2006

Molecular interactions between estrogen receptor and its ligand studied by the ab initio fragment molecular orbital method.

The ab initio fragment molecular orbital calculations were performed for molecular interactions of the whole estrogen receptor (ER) ligand-binding domain with a natural ligand, 17beta-estradiol (EST). The interaction energies of the ligand at the residue level were calculated using HF and MP2 methods with several basis sets. The charge-transfer (CT) interactions were also analyzed based on configuration analysis for fragment interaction. Strong electrostatic interactions were observed between the EST and surrounding charged/polarized residues, Glu353, Arg394, His524, and Thr347. Weak electrostatic and significant van der Waals dispersion interactions were observed between the EST and the many surrounding hydrophobic residues. Together with the experimental interpretations, both interactions equally contributed to the total binding energies, and it was found that the inclusion of electron correlation was essential to obtain an appropriate picture of the interaction. The strongest interaction energy was observed between Glu353 and the EST, and the CT interactions from the lone-pair orbital of the carbonyl oxygen of Glu353 to the sigma(OmicronEta) orbital of the hydroxyl group of EST were found to be important. The CT interactions from the lone-pair orbital of EST to the sigma(NuEta) of Arg394 and from the lone-pair orbital of EST to the sigma(NuEta) of His524 were also observed. These CT interactions occurred through the hydrogen-bond networks between the ER and EST. Therefore, electron donations from the ER to the EST and electron back-donations from EST to the ER were characteristic of ER-ligand binding. Our approach provides a powerful tool to understanding detailed molecular interactions at the quantum mechanical level.

Estradiol↗

PubMed2006

Synthesis of (Z)-alkene and (E)-fluoroalkene-containing diketopiperazine mimetics utilizing organocopper-mediated reduction-alkylation and diastereoselectivity examination using DFT calculations.

We have carefully examined the organocopper-mediated reduction-alkylation of gamma-acetoxy or gamma,gamma-difluoro-alpha,beta-unsaturated-delta-lactams for the synthesis of (Z)-alkene- or (E)-fluoroalkene-containing diketopiperazine mimetics. Reduction of acetates 2, 12, 14, and difluorolactam 18 with higher-order cuprate reagents (Me3CuLi2 x LiI x 3 LiBr), followed by trapping the resulting metal dienolate with an electrophile in a one-pot procedure gave alpha-alkylated-beta,gamma-unsaturated-delta-lactams in good yields. Because of side-chain steric repulsion, we found that alkylation using relatively large electrophiles such as BnBr gave mostly 3,6-trans isomers by kinetic trapping of metal enolates. On the other hand, MeI-mediated alkylations predominantly provided the unexpected 3,6-cis isomers despite the presence of a bulky benzyl side chain. Based on density functional theory calculations, we concluded that formation of the 3,6-cis isomers was due to the occurrence of oxa-pi-allyllithium complexes 29 and 31.

Alkenes↗

PubMed2006

Stereoselective synthesis of 3,6-disubstituted-3,6-dihydropyridin-2-ones as potential diketopiperazine mimetics using organocopper-mediated anti-SN2' reactions and their use in the preparation of low-molecule CXCR4 antagonists.

Organocopper-mediated anti-SN2' reactions of gamma-phosphoryloxy-alpha,beta-unsaturated-delta-lactams were used to prepare highly functionalized diketopiperazine mimetics. The substrate phosphates 24, 32, and 47 were prepared from alpha-amino acid-derived allylic alcohols 10 by a sequence of reactions that included ring-closing metathesis. In the reactions of phosphates with organocopper reagents, the addition of LiCl dramatically improved anti-SN2' selectivity, indicating that an organocopper cluster containing lithium chloride plays an important role in the determination of regioselectivity. This reaction system was applied to the preparation of novel low molecular weight CXCR4-chemokine receptor antagonists.

Copper↗

PubMed2006

All electron quantum chemical calculation of the entire enzyme system confirms a collective catalytic device in the chorismate mutase reaction.

To elucidate the catalytic power of enzymes, we analyzed the reaction profile of Claisen rearrangement of Bacillus subtilis chorismate mutase (BsCM) by all electron quantum chemical calculations using the fragment molecular orbital (FMO) method. To the best of our knowledge, this is the first report of ab initio-based quantum chemical calculations of the entire enzyme system, where we provide a detailed analysis of the catalytic factors that accomplish transition-state stabilization (TSS). FMO calculations deliver an ab initio-level estimate of the intermolecular interaction between the substrate and the amino acid residues of the enzyme. To clarify the catalytic role of Arg90, we calculated the reaction profile of the wild-type BsCM as well as Lys90 and Cit90 mutant BsCMs. Structural refinement and the reaction path determination were performed at the ab initio QM/MM level, and FMO calculations were applied to the QM/MM refined structures. Comparison between three types of reactions established two collective catalytic factors in the BsCM reaction: (1) the hydrogen bonds connecting the Glu78-Arg90-substrate cooperatively control the stability of TS relative to the ES complex and (2) the positive charge on Arg90 polarizes the substrate in the TS region to gain more electrostatic stabilization.

Bacillus subtilis↗

PubMed2006

The polarizable continuum model (PCM) interfaced with the fragment molecular orbital method (FMO).

The polarizable continuum model (PCM) for the description of solvent effects is combined with the fragment molecular orbital (FMO) method at several levels of theory, using a many-body expansion of the electron density and the corresponding electrostatic potential, thereby determining solute (FMO)-solvent (PCM) interactions. The resulting method, denoted FMO/PCM, is applied to a set of model systems, including alpha-helices and beta-strands of alanine consisting of 10, 20, and 40 residues and their mutants to charged arginine and glutamate residues. The FMO/PCM error in reproducing the PCM solvation energy for a full system is found to be below 1 kcal/mol in all cases if a two-body expansion of the electron density is used in the PCM potential calculation and two residues are assigned to each fragment. The scaling of the FMO/PCM method is demonstrated to be nearly linear at all levels for polyalanine systems. A study of the relative stabilities of alpha-helices and beta-strands is performed, and the magnitude of the contributing factors is determined. The method is applied to three proteins consisting of 20, 129, and 245 residues, and the solvation energy and computational efficiency are discussed.

Journal Article↗

PubMed2005

Ab initio fragment molecular orbital (FMO) method applied to analysis of the ligand-protein interaction in a pheromone-binding protein.

Full quantum computation of the electronic state of proteins has recently become possible by the advent of the ab initio fragment molecular orbital (FMO) method. We applied this method to the analysis of the interaction between the Bombyx mori pheromone-binding protein and its ligand, bombykol. The protein-ligand interaction of this molecular complex was minutely analyzed by the FMO method, and the analysis revealed several important interactions between the ligand and amino acid residues.

Animals↗

PubMed2005

Coupled-cluster theory based upon the fragment molecular-orbital method.

The fragment molecular-orbital (FMO) method was combined with the single-reference coupled-cluster (CC) theory. The developed method (FMO-CC) was applied at the CCSD and CCSD(T) levels of theory, for the cc-pVnZ family of basis sets (n=D,T,Q) to water clusters and glycine oligomers (up to 32 molecules/residues using as large basis sets as possible for the given system). The two- and three-body FMO-CC results are discussed at length, with emphasis on the basis-set dependence and three-body effects. Two- and three-body approximations based on interfragment distances were developed and the values appropriate for their accurate application carefully determined. The error in recovering the correlation energy was several millihartree for the two-body FMO-CC method and in the submillihartree range for the three-body FMO-CC method. In the largest calculations, we were able to perform the CCSD(T) calculations of (H2O)32 with the cc-pVQZ basis set (3680 basis functions) and (GLY)32 with the cc-VDZ basis set (712 correlated electrons). FMO-CC was parallelized using the upper level of the two-layer parallelization scheme. The computational scaling of the two-body FMO-CC method was demonstrated to be nearly linear. As an example of timings, CCSD(T) calculations of (H2O)32 with cc-pVDZ took 13 min on an eight node 3.2-GHz Pentium4 cluster.

Journal Article↗

PubMed2005

Multilayer formulation of the fragment molecular orbital method (FMO).

The fragment molecular orbital method (FMO) has been generalized to allow for multilayer structure. Fragments are assigned to layers, and each layer can be described with a different basis set and/or level of electron correlation. Interlayer boundaries are treated in the general spirit of the FMO method since they also coincide with some interfragment boundaries. The question of the one- and two-layer FMO accuracy dependence upon the fragmentation scheme is also addressed. The new method has been applied to predict the reaction barrier and the reaction heat for the Diels-Alder reaction with a representative set of reactants based on dividing fragments in two layers. The 6-31G* basis set has been used for the active site and the 6-31G*, 6-31G, 3-21G, and STO-3G basis sets have been used for the substituents. Different levels of electron correlation (RHF, B3LYP, and MP2) have been applied to layers in systematic fashion. The one-layer FMO errors in the reaction barrier and the reaction heat were 2.0 kcal/mol or less for all levels applied (RHF, B3LYP, and MP2), relative to full ab initio methods. For the two-layer method the error was found to be several kcal/mol. Benchmark calculations of the activation barrier for the decarboxylation of phenylcyanoacetate by beta-cyclodextrin demonstrated that the two-layer calculations are efficient, being 36 times faster than the regular DFT, as well as accurate, with the error being 1.0 kcal/mol.

Models, Chemical↗

PubMed2005

Multiconfiguration self-consistent-field theory based upon the fragment molecular orbital method.

The fragment molecular orbital (FMO) method was combined with the multiconfiguration self-consistent-field (MCSCF) theory. One- and two-layer approaches were developed, the former involving all dimer MCSCF calculations and the latter limiting MCSCF calculations to a small part of the system. The accuracy of the two methods was tested using the six electrons in six orbitals complete active space type of MCSCF and singlet spin state for phenol+(H(2)O)(n), n=16,32,64 (6-31G( *) and 6-311G( *) basis sets); alpha helices and beta strands of phenylalanine-(alanine)(n), n=4,8,16 (6-31G( *)). Both double-zeta and triple-zeta quality basis sets with polarization were found to have very similar accuracy. The error in the correlation energy was at most 0.000 88 a.u., the error in the gradient of the correlation energy was at most 6.x10(-5) a.u./bohr and the error in the correlation correction to the dipole moment was at most 0.018 D. In addition, vertical singlet-triplet electron excitation energies were computed for phenol+(H(2)O)(n), (n=16,32,64), 6-31G( *), and the errors were found to be at most 0.02 eV. Approximately linear scaling was observed for the FMO-based MCSCF methods. As an example, an FMO-based MCSCF calculation with 1262 basis functions took 98 min on one 3.0 GHz Pentium4 node with 1 Gbyte RAM.

Journal Article↗

PubMed2005

Ab initio quantum mechanical study of the binding energies of human estrogen receptor alpha with its ligands: an application of fragment molecular orbital method.

We have theoretically examined the relative binding affinities (RBA) of typical ligands, 17beta-estradiol (EST), 17alpha-estradiol (ESTA), genistein (GEN), raloxifene (RAL), 4-hydroxytamoxifen (OHT), tamoxifen (TAM), clomifene (CLO), 4-hydroxyclomifene (OHC), diethylstilbestrol (DES), bisphenol A (BISA), and bisphenol F (BISF), to the alpha-subtype of the human estrogen receptor ligand-binding domain (hERalpha LBD), by calculating their binding energies. The ab initio fragment molecular orbital (FMO) method, which we have recently proposed for the calculations of macromolecules such as proteins, was applied at the HF/STO-3G level. The receptor protein was primarily modeled by 50 amino acid residues surrounding the ligand. The number of atoms in these model complexes is about 850, including hydrogen atoms. For the complexes with EST, RAL, OHT, and DES, the binding energies were calculated again with the entire ERalphaLBD consisting of 241 residues or about 4000 atoms. No significant difference was found in the calculated binding energies between the model and the real protein complexes. This indicates that the binding between the protein and its ligands is well characterized by the model protein with the 50 residues. The calculated binding energies relative to EST were very well correlated with the experimental RBA (the correlation coefficient r=0.837) for the ligands studied in this work. We also found that the charge transfer between ER and ligands is significant on ER-ligand binding. To our knowledge, this is the first achievement of ab initio quantum mechanical calculations of large molecules such as the entire ERalphaLBD protein.

Binding Sites↗

PubMed2004

Second order Møller-Plesset perturbation theory based upon the fragment molecular orbital method.

The fragment molecular orbital (FMO) method was combined with the second order Møller-Plesset (MP2) perturbation theory. The accuracy of the method using the 6-31G(*) basis set was tested on (H(2)O)(n), n=16,32,64; alpha-helices and beta-strands of alanine n-mers, n=10,20,40; as well as on (H(2)O)(n), n=16,32,64 using the 6-31 + + G(**) basis set. Relative to the regular MP2 results that could be afforded, the FMO2-MP2 error in the correlation energy did not exceed 0.003 a.u., the error in the correlation energy gradient did not exceed 0.000 05 a.u./bohr and the error in the correlation contribution to dipole moment did not exceed 0.03 debye. An approximation reducing computational load based on fragment separation was introduced and tested. The FMO2-MP2 method demonstrated nearly linear scaling and drastically reduced the memory requirements of the regular MP2, making possible calculations with several thousands basis functions using small Pentium clusters. As an example, (H(2)O)(64) with the 6-31 + + G(**) basis set (1920 basis functions) can be run in 1 Gbyte RAM and it took 136 s on a 40-node Pentium4 cluster.

Journal Article↗

PubMed2004

A new hierarchical parallelization scheme: generalized distributed data interface (GDDI), and an application to the fragment molecular orbital method (FMO).

A two-level hierarchical scheme, generalized distributed data interface (GDDI), implemented into GAMESS is presented. Parallelization is accomplished first at the upper level by assigning computational tasks to groups. Then each group does parallelization at the lower level, by dividing its task into smaller work loads. The types of computations that can be used with this scheme are limited to those for which nearly independent tasks and subtasks can be assigned. Typical examples implemented, tested, and analyzed in this work are numeric derivatives and the fragment molecular orbital method (FMO) that is used to compute large molecules quantum mechanically by dividing them into fragments. Numeric derivatives can be used for algorithms based on them, such as geometry optimizations, saddle-point searches, frequency analyses, etc. This new hierarchical scheme is found to be a flexible tool easily utilizing network topology and delivering excellent performance even on slow networks. In one of the typical tests, on 16 nodes the scalability of GDDI is 1.7 times better than that of the standard parallelization scheme DDI and on 128 nodes GDDI is 93 times faster than DDI (on a multihub Fast Ethernet network). FMO delivered scalability of 80-90% on 128 nodes, depending on the molecular system (water clusters and a protein). A numerical gradient calculation for a water cluster achieved a scalability of 70% on 128 nodes. It is expected that GDDI will become a preferred tool on massively parallel computers for appropriate computational tasks.

Journal Article↗

PubMed2004

The importance of three-body terms in the fragment molecular orbital method.

A previously proposed two-body fragment molecular orbital method based on the restricted Hartree-Fock (RHF) method was extended to include explicit three-body terms. The accuracy of the method was tested on a set of representative molecules: (H(2)O)(n), n=16, 32, and 64, as well as alpha and beta n-mers of alanine, n=10, 20, and 40, using STO-3G, 3-21G, 6-31G, and 6-31++G(**) basis sets. Two- and three-body results are presented separately for assigning one and two molecules (or residues) per fragment. Total energies are found to differ from the regular RHF method by at most DeltaE(2/1)=0.06, DeltaE(2/2)=0.04, DeltaE(3/1)=0.02, and DeltaE(3/2)=0.003 (a.u.); rms energy gradients differ by at most DeltaG(2/1)=0.0015, DeltaG(2/2)=0.000 75, DeltaG(3/1)=0.000 20, and DeltaG(3/2)=0.000 10 (a.u./bohr), and rms dipole moments are reproduced with at most deltaD(2/1)=3.7, deltaD(2/2)=3.4, deltaD(3/1)=2.6, and deltaD(3/2)=3.1 (%) relative error, where the subscript notation n/m refers to the n-body method based on m molecules (residues) per fragment. A few of the largest three-body calculations were performed with a separated trimer approximation, which presumably somewhat lowered the accuracy of mostly dipole moments which are very sensitive to slight variations in the density distribution. The proposed method is capable of providing sufficient chemical accuracy while providing detailed information on many-body interactions.

Chemistry, Physical↗