Scale Modeling of Medical Molecular Systems

  • Tatsuhiko Kikkou
  • Shinichiro Iwabuchi
  • Osamu Matsumoto

Abstract

Human body is mainly made by several biomacromolecules. The mal-function of proteins and nucleic acids set up our diseases; it would be considered that ca. 70% of human diseases occurred by that of receptor proteins, especially. Therefore the clarification of relationship between structure and function on bio-macromolecule is one of the highest priorities in the pharmaceutical science field. Nowadays, several technical innovations on structural biology (sample expression by genetic technology, innovation of measurements; i.e. SOR (Synchrotron Orbit Radiation) or giant NMR (Nuclear Magnetic Resonance) and so on, structural analysis calculation by super computer) make easy to analyze stereo structure of macromolecules. However, number of determined structures would not clear up the relationship between structure and function on biomacromolecules systematically.

On the other hand, the author found the molecular model on biomacromolecule resembles a “space truss structure” in the Building Engineeringtectonics or a “space link” in the Mechanics. Therefore the molecular model must be obeyed by the rules on these Kinematics at least, and a real molecule may be obeyed also. The simplest principle, the balance of internal degree of freedom and number of restraints in the molecule, would be determined the molecular stiffness or flexibility or mechanism. DNA and some protein structures will be discussed under the principle.

Keywords

Medical molecular system degree of freedom protein nucleic acid enzyme receptor 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Watson, J. D., Crick, F. H. C. “Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid”. Nature, 4356 April 25, (1953).Google Scholar
  2. 2.
    Matsumoto O., Taga T., Matsushima M., Higashi T., Machida K. “Multiple binding of inhibitors in the complex formed by bovine trypsin and fragments of a synthetic inhibitor, 4-[4-(N,N-dimethylcarbamoxylmethoxycarbonylmethyl)phenoxycarbonylphenyl]guanidinium methanesulfonate (FOY-305)”. Chem Pharm Bull (Tokyo). 38:2253–5. (1990).Google Scholar
  3. 3.
    Matsumoto, O., Taga T., Higashi T., Matsushima M., Machida K. “Complex formation by bovine trypsin and a tetrapeptide (Leu-Arg-Pro-Gly-NH2): X-ray structure analysis of the complex in the orthorhombic crystal form with low molecular packing density”. J. Protein Chem. 5: 589–93 (1990).CrossRefGoogle Scholar
  4. 4.
    Vassylyev, D., G. Katayanagi, K. Ishikawa, K. Tsujimoto-Hirano, M. Danno, M. Pahler, A., Matsumoto, O., Matsushima, M., Yoshida, H., Morikawa, K. “Crystal structures of ribonuclease F1 of Fusarium moniliforme in its free form and in complex with 2’GMP”. J. Mol. Biol. 230: 979–96 (1993).CrossRefGoogle Scholar
  5. 5.
    Morikawa K., Matsumoto O., Tsujimoto M., Katayanagi K., Ariyoshi M., Doi T., Ikehara M., Inaoka T., Ohtsuka E. “X-ray structure of T4 endonuclease V: an excision repair enzyme specific for a pyrimidine dimer”. Science 256: 523–6. (1992).CrossRefGoogle Scholar
  6. 6.
    Morikawa K., Ariyoshi M., Vassylyev D.G., Matsumoto O., Katayanagi K., Ohtsuka E. “Crystal structure of a pyrimidine dimer-specific excision repair enzyme from bacteriophage T4: Refinement at 1.45 A and X-ray analysis of the three active site mutants”., J. Mol. Biol. 249: 360–75 (1995).CrossRefGoogle Scholar
  7. 7.
    Pauling, L., Corey, R. B., Branson, H. R. “The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain”., Proc. Natl. Acad. Sci. USA 37: 205–11 (1951).CrossRefGoogle Scholar
  8. 8.
    Dickerson, R. E., Geis, I. The Structure and Action of Proteins, Harper & Row, New York, 1969.Google Scholar
  9. 9.
    Watson, J. D. The Double Helix, Atheneum, New York, 1967.Google Scholar
  10. 10.
    Drew, H. R., Dickerson, R. E. “Structure of a DNA dodecamer. III. Geometry of hydration”. J. Mol. Biol. 55: 379–400 (1981).Google Scholar
  11. 11.
    Conner, B. N., Takano, T., Tanaka, S., Itakura, K., Dickerson, R. E. “The molecular structure of d(ICpCpGpG), a fragment of right-handed double helical A-DNA”. Nature, 295: 294–9. (1982).CrossRefGoogle Scholar
  12. 12.
    Umehara, T., Kuwabara, S., Mashimo, S., Yagihara, S. “Dielectric study on hydration of B-, A-, and Z-DNA”. Biopolymers 30: 649–56 (1990).CrossRefGoogle Scholar
  13. 13.
    Sakurai, F., Inoue, R., Nishino, Y., Okuda, A., Matsumoto, O., Taga, T., Yamashita, F., Takakura, Y., Hashida, M. “Effect of DNA/liposome mixing ratio on the physicochemical characteristics, cellular uptake and intracellular trafficking of plasmid DNA/cationic liposome complexes and subsequent gene expression”. J Control Release. 66: 255–69 (2000)CrossRefGoogle Scholar
  14. 14.
    Sakurai, F., Nishioka, T., Saito, H., Baba, T., Okuda, A., Matsumoto, O., Taga, T., Yamashita, F., Takakura, Y., Hashida, M. “Interaction between DNA-cationic liposome complexes and erythrocytes is an important factor in systemic gene transfer via the intravenous route in mice: the role of the neutral helper lipid”. Gene Ther. 6: 677–86. (2001).CrossRefGoogle Scholar
  15. 15.
    Lin, Z., Wang, C., Feng, X., Lin, M., Li, J., Bai, C. “The observation of the local ordering characteristics of spermidine-condensed DNA: atomic force microscopy and polarizeing microscopy studies”. Nucleic Acids Res. 26: 3228–34 (1998).CrossRefGoogle Scholar
  16. 16.
    Okamoto, T., Murayama, Y., Hayashi, Y., Inagaki, M., Ogata, E., Nishimoto, I. “Identification of a Gs activator region of the beta 2-adrenergic receptor that is autoregulated via protein kinase A-dependent phosphorylation”. Cell 67: 723–30 (1991).CrossRefGoogle Scholar
  17. 17.
    Okuda, A., Matsumoto, O., Akaji, M., Taga, T., Ohkubo, T., Kobayashi, Y. “Solution structure of intracellular signal-transducing peptide derived from human beta2-adrenergic receptor”. Biochem. Biophys. Res. Commun. 291:1297–301 (2002).CrossRefGoogle Scholar
  18. 18.
    Kikkou, T., Matsumoto, O., Ohkubo, T., Kobayashi, Y., Tsujimoto, G. “NMR structure of an intracellular loop peptide derived from prostaglandin EP3alpha receptor”. Biochem Biophys Res Commun. 345: 933–7 (2006).CrossRefGoogle Scholar
  19. 19.
    Hasegawa, H., Negishi, M., Ichikawa, A. “Two isoforms of the prostaglandin E receptor EP3 subtype different in agonist-independent constitutive activity”. J. Biol. Chem. 271: 1857–60 (1996).CrossRefGoogle Scholar
  20. 20.
    Negishi, M., Hasegawa, H., Ichikawa, A. “Prostaglandin E receptor EP3gamma isoform, with mostly full constitutive Gi activity and agonist-dependent Gs activity”. FEBS Lett. 386: 165–8. (1996).CrossRefGoogle Scholar
  21. 21.
    Ichikawa, A., Negishi, M., Hasegawa, H. “Three isoforms of the prostaglandin E receptor EP3 subtype different in agonist-independent constitutive Gi activity and agonist-dependent Gs activity”. Adv Exp Med Biol. 433: 239–42 (1997).Google Scholar
  22. 22.
    Hizaki, H., Hasegawa, H., Katoh, H., Negishi, M., Ichikawa, A. “Functional role of carboxyl-terminal tail of prostaglandin EP3 receptor in Gi coupling”. FEBS Lett. 414: 323–6 (1997).CrossRefGoogle Scholar
  23. 23.
    Lambright, D. G., Noel, J. P., Hamm, H. E., Siegler, P. B. “Structural determinants for activation of the alpha-subunit of a heterotrimeric G protein”. Nature 369: 621–8 (1994).Google Scholar
  24. 24.
    Hangai, Y., Kawaguchi, K. “Keitai Kaiseki”. Baifukan, Tokyo, 1991, p. 67 (in Japanese).Google Scholar
  25. 25.
    Marquart, M., Walter, J., Deisenhofer, J., Bode, W., Huber, R. “The Geometry of the Reactive Site and of the Peptide Groups in Trypsin, Trypsinogen and its Complexes with Inhibitors”. Acta Crystallogr., Sect. B v39: 480 (1983).CrossRefGoogle Scholar
  26. 26.
    Takeuchi, Y., Nonaka, T., Nakamura, K. T., Kojima, S., Miura, K.-I., Mitsui, Y. “Crystal structure of an engineered subtilisin inhibitor complexed with bovine trypsin”. Proc. Natl. Acad. Sci. USA 89: 4407–11 (1992).Google Scholar
  27. 27.
    Matsumoto, O., Taga, T., Higashi, T., Matsushima, M., Machida, K. “Complex formation by bovine trypsin and a tetrapeptide (Leu-Arg-Pro-Gly-NH2): X-ray structure analysis of the complex in the orthorhombic crystal form with low molecular packing density”. J. Protein Chem. 9: 589–593 (1990).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Tatsuhiko Kikkou
  • Shinichiro Iwabuchi
  • Osamu Matsumoto
    • 1
  1. 1.Department of Pharmaceutical SciencesChiba Institute of ScienceChoshiJapan 288-0025

Personalised recommendations