Chapter 19
Analysis of Water Molecules in the Hras-GTP
and GDP Complexes with Molecular Dynamics
Simulations
Takeshi Miyakawa, Ryota Morikawa, Masako Takasu, Akira Dobashi,
Kimikazu Sugimori, Kazutomo Kawaguchi, Hiroaki Saito, and Hidemi Nagao
Abstract In the Hras-GTP and GDP complexes, the coordination bonds between
Mg 2+ and oxygen atoms are very important. In this study, we use AMBER03 and
our calculated force field parameters, and perform MD simulations of Hras-GTP and
GDP complexes with water solvents. It is shown that the number of water molecules
in the first hydration sphere is larger in GDP than in GTP. The duration time and the
direction of water molecules in the first hydration sphere in GTP is not so different
from those in GDP. It is shown that water molecules are distributed evenly around
PG, although they are not distributed evenly around PB. This difference can be the
reason why the hydrolysis of GTP in Hras-GTP is easier than the hydrolysis of GDP
in Hras-GDP.
19.1 Introduction
Hras is a product of proto-oncogene Hras, and is included in the signaling process
to induce the cell division and cell differentiation. Hras is one of G-proteins, which
act as molecular switch.
In inactive state, Hras forms a complex with GDP (guanosine diphosphate). Hras
is in inactive state if Hras is in non-cancerous cell and if cell division is not needed.
When EGF (epidermal growth factor) binds EGFR (epidermal growth factor receptor), the signal of cell division and differentiation propagates to Hras. When the
signal reaches Hras, GEF (guanine nucleotide exchange factor) binds Hras. This
promotes the dissociation of GDP from Hras. Because the concentration of GTP
(guanosine triphosphate) is much higher than the concentration of GDP in cytoplasm, active Hras-GTP complex is made. Because Hras-GTP has higher affinity to
Hras binding protein than Hras-GDP, the signal of cell division and cell differentiation propagates to nuclei through the path including the Hras binding protein. When
the signal of cell division and cell differentiation reaches nuclei, the expression of
genes which are coding the protein needed for cell division and cell differentiation
T. Miyakawa (B)
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi,
Hachioji, Tokyo 192-0392, Japan
e-mail: takeshi@toyaku.ac.jp
M. Hotokka et al. (eds.), Advances in Quantum Methods and Applications in
Chemistry, Physics, and Biology, Progress in Theoretical Chemistry and Physics 27,
DOI 10.1007/978-3-319-01529-3_19,
© Springer International Publishing Switzerland 2013
351
Analysis of Water Molecules in the Hras-GTP
and GDP Complexes with Molecular Dynamics
Simulations
Takeshi Miyakawa, Ryota Morikawa, Masako Takasu, Akira Dobashi,
Kimikazu Sugimori, Kazutomo Kawaguchi, Hiroaki Saito, and Hidemi Nagao
Abstract In the Hras-GTP and GDP complexes, the coordination bonds between
Mg 2+ and oxygen atoms are very important. In this study, we use AMBER03 and
our calculated force field parameters, and perform MD simulations of Hras-GTP and
GDP complexes with water solvents. It is shown that the number of water molecules
in the first hydration sphere is larger in GDP than in GTP. The duration time and the
direction of water molecules in the first hydration sphere in GTP is not so different
from those in GDP. It is shown that water molecules are distributed evenly around
PG, although they are not distributed evenly around PB. This difference can be the
reason why the hydrolysis of GTP in Hras-GTP is easier than the hydrolysis of GDP
in Hras-GDP.
19.1 Introduction
Hras is a product of proto-oncogene Hras, and is included in the signaling process
to induce the cell division and cell differentiation. Hras is one of G-proteins, which
act as molecular switch.
In inactive state, Hras forms a complex with GDP (guanosine diphosphate). Hras
is in inactive state if Hras is in non-cancerous cell and if cell division is not needed.
When EGF (epidermal growth factor) binds EGFR (epidermal growth factor receptor), the signal of cell division and differentiation propagates to Hras. When the
signal reaches Hras, GEF (guanine nucleotide exchange factor) binds Hras. This
promotes the dissociation of GDP from Hras. Because the concentration of GTP
(guanosine triphosphate) is much higher than the concentration of GDP in cytoplasm, active Hras-GTP complex is made. Because Hras-GTP has higher affinity to
Hras binding protein than Hras-GDP, the signal of cell division and cell differentiation propagates to nuclei through the path including the Hras binding protein. When
the signal of cell division and cell differentiation reaches nuclei, the expression of
genes which are coding the protein needed for cell division and cell differentiation
T. Miyakawa (B)
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi,
Hachioji, Tokyo 192-0392, Japan
e-mail: takeshi@toyaku.ac.jp
M. Hotokka et al. (eds.), Advances in Quantum Methods and Applications in
Chemistry, Physics, and Biology, Progress in Theoretical Chemistry and Physics 27,
DOI 10.1007/978-3-319-01529-3_19,
© Springer International Publishing Switzerland 2013
351