|Affiliation||Department of Computer Science and Engineering|
|Fields of Research||Quantum biology / Computational science / Biological information science|
|Degree||Ph.D. (Tsukuba University)|
|Academic Societies||Physical society / Biophysical society / Japan Society of Molecular Science / Chem-Bio Informatics Society|
Please append ".tut.ac.jp" to the end of the address above.
|Laboratory website URL||http://www.klab.cs.tut.ac.jp|
|Researcher information URL（researchmap）||Researcher information|
In our laboratory, the following research subjects are investigated by using our developed ab-initio molecular simulations.
(1) Elucidation of the DNA transcription mechanism controlled by lactose-repressor protein and catabolite activator protein
(2) Design of new medicines inhibiting cancer metastasis based on the quantum mechanical calculations
(3) Elucidation of the attacking mechanism of radicals to DNA duplex by the first-principle density functional calculations
(4) Design of new medicines for Alzheimer's disease blocking aggregation of amyloid-beta proteins
(5) In silico drug design for treating many kinds of diseases based on ab initio molecular simulations
Theme1：Ab initio molecular simulations on the attacking mechanism of radicals to DNA base pairs
To elucidate the influence of solvating water molecules on the attacking mechanism of OH-radical to DNA base pairs (G–C and A–T), we investigated the reaction mechanism in water, by the use of the density functional theory (DFT) calculations by considering water molecules explicitly. The results reveal that OH-radical is stabilized near the NH2 group of cytosine of G–C by the water molecules hydrogen bonded to the OH-radical and that 2.5 kcal/mol activation free energy is needed for extracting the hydrogen atom from the NH2 group. On the other hand, OH-radical prefers to extract the hydrogen atom from the NH2 group of adenine in the solvated A–T. As for the tautomeric reaction of the base pair attacked by OH-radical, we found the transition state for the reaction from A to T to its tautomeric form A*–T*, although the activation free energy is rather large (25 kcal/mol). By contrast, in the G–C attacked by OH-radical, one central proton can move freely from G to C, resulting in the tautomeric form G*–C*. Therefore, our DFT calculations in explicit water molecules elucidate the possibility that the attacking of OH-radical to G–C causes its tautomeric form G*–C*, while A–T attacked by OH-radical cannot transform into its A*–T* form in a normal condition. This finding will be useful for predicting the effect of OH radical on the genetic information recorded in DNA base sequences.
Selected publications and works
(1)"Influence of solvating water molecules on the attacking mechanisms of OH-radical to DNA base pairs: DFT calculations in explicit waters",
Shimamura, K.; Okutsu, N.; Shimizu, E.; Shulga, S.; Blume, Y.B.; Danilov, V.I.; Kurita, N., Structural Chemistry, 2016, 27, 1793-1806.
(2)"Attacking mechanism of hydroxyl radical to DNA base-pair: density functional study in vacuum and in water",
Shimizu, E.; Tokuyama, Y.; Okutsu, N.; Nomura, K.; Danilov, V. I.; Kurita, N., J. of Biomolecular Structure and Dynamics, 2015, 33, 158-166.
(3)"DFT study on reaction mechanism of DNA base pair with hydroxyl radical", Shimizu, E.; Hoshino, R.; Nomura, K.; Danilov, V. I.; Kurita, N., J. Modern Physics, Special issue on DFT, 2013, 4, 442-451.
Theme2：Elucidation of transcription mechanism controlled by LacR and CAP proteins and ligand
Lactose repressor protein (LacR) plays an essential role in controlling the transcription mechanism of genomic information from DNA to mRNA. It has been elucidated that a ligand binding to LacR regulates allosterically the specific interactions between LacR and operator DNA. However, the effect of the ligand binding on the specific interactions has not been clarified at an atomic level. In this study, we performed classical molecular dynamics (MD) and ab initio fragment molecular orbital simulations to elucidate the effect of ligand binding at atomic and electronic levels. The MD simulations for the solvated complexes with LacR-dimer, DNA and ligand demonstrate that the binding of an inducer IPTG to LacR-dimer significantly changes the structure of LacR-monomer to cause strong interactions between LacR-monomers, resulting in weakening the interactions between LacR-dimer and DNA. In contrast, the binding of an anti-inducer ONPF to LacR-dimer was found to enhance the interactions between LacR-dimer and DNA. These findings are consistent with the functions of IPTG and ONPF as an inducer and an anti-inducer, respectively. We therefore proposed a simplified model for the effect of
the ligand binding on the specific interactions between LacR-dimer and DNA.
Selected publications and works
(1)"Change in specific interactions between lactose repressor protein and DNA induced by ligand binding: molecular dynamics and molecular orbital calculations", Matsushita, Y.; Murakawa, T.; Shimamura, K.; Ohyama, T.; Oishi, M.; Kurita, N., Molecular Simulation, 2015, 42, 242-256.
(2)"Specific interactions between DNA and regulatory protein controlled by ligand-binding: ab initio molecular simulation", Matsushita, Y.; Murakawa, T.; Shimamura, K.; Ohyama, T.; Oishi, M.; Kurita, N.,
AIP Conference Proceedings 1649, 121 (2015); doi: 10.1063/1.4913556.
(3)"Specific interactions between lactose repressor protein and DNA affected by ligand binding: ab initio molecular orbital calculations",
Ohyama, T.; Hayakawa, M.; Nishikawa, S.; Kurita, N., Journal of Computational Chemistry, 2011, 32, 1661-1670.
Theme3：Molecular simulations for proposing novel potent inhibitors against cancer invasion
A variety of proteases play important roles in cancer invasion and metastasis. Among these proteases, urokinase-type plasminogen activator (uPA) is particularly important, since its specific binding to the receptor (uPAR) existing on the surface of a cancer cell is considered to be a trigger for cancer invasion. It is thus expected that the blocking of the binding can inhibit cancer invasion in the cancer patients and improve their prognosis dramatically. To develop a potent inhibitor for the binding, many types of peptides of amino acids were produced and their effect on the cancer invasion was investigated in the previous biochemical experiments. On the other hand, our previous ab initio molecular simulations have clarified that some amino acid residues of uPA play important roles in the specific binding between uPA and uPAR. In the present study, we propose some peptides composed of these important residues and investigate the specific interactions and the binding affinity between uPAR and the peptides at an electronic level, using ab initiomolecular simulations. Base on the results simulated, we elucidate which peptide can bind more strongly to uPAR and propose a novel potent peptide which can inhibit the binding between uPAR and uPA efficiently.
Selected publications and works
(1)"Ab initio molecular simulations for proposing novel peptide inhibitors blocking the ligand-binding pocket of urokinase receptor",
Mizushima, T.; Sugimoto, T.; Kasumi, T.; Araki, K.; Kobayashi, H.; Kurita, N., Journal of Molecular Modeling, 2014, 20: 2292 (11page).
(2)"The effects of vitronectin on specific interactions between urokinase-type plasminogen activator and its receptor: Ab initio molecular orbital calculations", Kasumi, T.; Araki, K.; Ohyama, T.; Tsuji, S.; Yoshikawa, E.; Kobayashi, H.; Kurita, N., Molecular simulation, 2013, 39, 769-779.
(3)"Effect of amino-acid mutation on specific interactions between urokinase-type plasminogen activator and its receptor: ab initio molecular orbital calculations", Tsuji, S.; Kasumi, T.; Nagase, K.; Yoshikawa, E.; Kobayashi, H.; Kurita, N., Journal of Molecular Graphics and Modeling, 2011, 29, 975-984.
Title of class
Bioinformatics / Intelligent information / Linear Algebra / Quantum biology / Advanced Quantum and Life Sciences for Informatics
Others (Awards, Committees, Board members)
● Molecular simulations for elucidating the aggregation mechanism of Ab peptides and proposing novel potent medicine treating Alzheimer's disease [Chem. Phys. Lett., 2017, 672, 13-20; Chem. Phys. Lett., 2015, 633, 139-145; Chem. Phys. Lett.,2013, 577, 131-137.]
● Ab initio molecular simulations on the specific interactions between vitamin-D receptor and its ligand [J. Steroid BioChem. & Molecular Biology, 2017, 171, 75-79; J. Mol. Graphics & Modeling, 2018, 80, 320-326; Chem-Bio. Informatics Journal, 2018, 18, 32-43.]
● Ab initio molecular simulations on the mutation mechanism of DNA base pairs [J. Phys. Chem. A, 2009, 113, 2233-2235.]
● Elucidation of specific interactions between aryl hydrocarbon receptor and dioxin by molecular simulations [J. Mol. Graphics & Modeling, 2010, 29, 197-205.]