@misc{oai:ir.soken.ac.jp:00000352,
 author = {Saree, Phongphanphanee and セリー, フォン ファンファニー and PHONGPHANPHANEE, Saree},
 month = {2016-02-17, 2016-02-17},
 note = {Aquaporins (AQPs), known as the water channel, are membrane proteins that can conduct water across cell membrane. Then they play an important role to maintain the homeostasis of a cell AQPs function not only as a water channel, but several members in the aquaporin family are also permeable by glycerol,  urea ammonia and other molecules. In spite that intensive efforts have been devoted to clarify the molecular mechanism of the aquaporin functions, there are many questions remained unanswered. Among the questions, the followings are most sharply focused in the experimental and as well as theoretical studies: 1) what is the role of R189 in the gating mechanism of aquaporins? 2) Why protons do not permeate through the channels, while water does? 3) Why both cations and anions are prohibited to transmit through the channels? And 4) Do small molecules other than water, such as, CO2 and NH3, permeate through AQP1? <br />　　　In the thesis work, he studied the molecular mechanism of aquaporin functions based on the RISM and 3D-RISM theories, and tied to answer the questions with respect to the molecular mechanism of aquaporins listed above. The RISM and 3D-RISM theories are the statistical mechanical integral equation theories of molecular liquids which have been developed by Hirata's group. The theories enable one to calculate the three dimensional distribution of water as well as other solute molecules around and inside a protein in aqueous solution.<br />  　　　For study the gating mechanism, he had calculated the distribution of water in AQPZ by using the RISM/3DRISM method. The positions of the water molecules inside some cavities of the protein, which have not been identified by the experiments, are also reported. The density profiles of water inside the channels with four different conformations, one open and three closed, have demonstrated good agreement with the experimental data. The water molecures distribute continuously along the channel in the open conformation, whereas the distributions in the closed conformations are interrupted by the gap at the location of the side chain R189. The results indicate that water cannot pass through the AQPZ channel in its close conformation. The results confirm the experimental postulate for the role of R189 in the gating mechanism of AQPZ.<br />  　　　The mechanism underlying the proton exclusion from AQP1 and GlpF has also elucidated in this work. It is found that the mechanisms to exclude the proton transport through AQP1 and GlpF are different. In AQP1 the hydronium ion is banned in a wide area from the NPA regron to the SF region, which is equivalent with the existence of the high positive barrier in the potential mean of force (PMF) along the entire channel. The proton cannot transport across this barrier. The high positive electrostatic potential is the primary cause to the high positive barrier in PMF. In GlpF, the electrostatic potential inside the channel is not as high as in AQP1. Hydronium ions can be distributed almost throughout the channel except the SF region; there is a small gap of distribution of hydronium ion at this region. The electrostatic potential itself cannot completely prevent protons from transportation because a proton may jump across the gap of distribution around SF area due to the Grotthuss mechanism. His analysis of the distribution functions has clarified that the hydrogen-bonded chain of water in the channel was disrupted due to the bipolar coordination of water molecules to the atoms in the side chains, which in turn interrupts the Grothuss mechanism to take place. It was concluded that the two mechanisms, electrostatic repulsion and bipolar coordination of orientation of water, are the causes to prevent the proton from transporting in GlpF.<br />  　　　In order to clarify the mechanism of ion exclusions from AQP1 and GlpF, he has calculated the distribution functions and PMF of ions, including cations, sodium and hydronium ions, and anion, chloride ion, in both channels. The distributions and PMF of both cations are similar. The results indicate that different mechanisms are working on the exclusion of cations and anion. In AQP1, there is a large gap in the distribution of each cation, spanning from SF to NPA regions. The gap in the distribution is equivalent to the high positive potential in PMF. The cations are excluded from the channel due to this high potential barrier. The essential cause of the barrier is the electrostatic field produced by protein. For the case of anion, the gap in the distribution is much narrower than the cations, which is limited at the SF region. This gap in the distribution corresponds to a high positive potential in PMF. Unlike the case of cations, the barrier is created by the steric effect due to the bulkiness of the ion, not by the electrostatic repulsion between the ion and channel atoms. Unlike AQP1, the distribution of cations in GlpF has three large minimums, corresponding to the three positive barriers in PMF. The height of the barriers is lower than those in AQP1 due to weaker electrostatic potential inside the channel. These barriers prevent the cations from transmitting across the channel. On the other hand, PMF of the anion is negative throughout the channel, and it has a deep well at the SF region. This result suggests another mechanism for the exclusion of ion transport through the channel. The anion is trapped at the SF region due to the strong electrostatic "attraction," which prevents the ion from permeating across the channel.<br />　　　To know whether the gas molecules can permeate through AQP or not, he has presented the results of the distribution and PMF of CO<small>2</small> and NH<small>3</small> in both central channel and water channel of AQP1. The results show that CO<small>2</small> and NH<small>3</small> cannot permeate through the central channel of the tetramer. In the water channel, the distribution function of CO<small>2</small> is discontinuous; it is interrupted by a gap. The corresponding PMF show a very high positive potential barrier at the gap area. The results suggest that CO<small>2</small> is prevented from transporting through the water channel. The distributions of NH<small>3</small> is similar to that of water, however the PMFs of both are different at R197 area. At this area PMF of NH<small>3</small> rises up to the peak whereas that of water falls down to the minimum. The height of the peak of PMF of NH<small>3</small>, ～2.5 kJ/mol, is simlar to the thermal energy. It suggests that NH<small>3</small> has possibility to transport though the channel, although its permeability is lower than water.<br /> 　　　In conclusion, he has applied the statistical mechanics theories of liquid to explore the mechanism of  transportation of solute through the AQPs. The result of distribution of water in AQPZ give a good agreement with experimental data and confirm the role R189 side chain on opening and closing channel. He also clarified the mechanism of proton and ions exclusion in AQPs, and proposes the new mechanism to prevent anion to transport through GlpF. Furthermore, he also showed that NH<small>3</small> can permeate through AQP1 but CO<small>2</small> can not., 総研大甲第1189号},
 title = {Conduction Mechanism of Aquaporin Channels Studied by the Statistical Mechanics of Liquids},
 year = {}
}