{"created":"2023-06-20T13:22:04.726018+00:00","id":2460,"links":{},"metadata":{"_buckets":{"deposit":"37f081b5-b55b-4fec-b5a1-23566c9de416"},"_deposit":{"created_by":21,"id":"2460","owners":[21],"pid":{"revision_id":0,"type":"depid","value":"2460"},"status":"published"},"_oai":{"id":"oai:ir.soken.ac.jp:00002460","sets":["2:427:10"]},"author_link":["0","0","0"],"item_1_creator_2":{"attribute_name":"著者名","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"清田, 泰臣"}],"nameIdentifiers":[{"nameIdentifier":"0","nameIdentifierScheme":"WEKO"}]}]},"item_1_creator_3":{"attribute_name":"フリガナ","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"キヨタ　, ヤスオミ"}],"nameIdentifiers":[{"nameIdentifier":"0","nameIdentifierScheme":"WEKO"}]}]},"item_1_date_granted_11":{"attribute_name":"学位授与年月日","attribute_value_mlt":[{"subitem_dategranted":"2011-03-24"}]},"item_1_degree_grantor_5":{"attribute_name":"学位授与機関","attribute_value_mlt":[{"subitem_degreegrantor":[{"subitem_degreegrantor_name":"総合研究大学院大学"}]}]},"item_1_degree_name_6":{"attribute_name":"学位名","attribute_value_mlt":[{"subitem_degreename":"博士（理学）"}]},"item_1_description_12":{"attribute_name":"要旨","attribute_value_mlt":[{"subitem_description":"&nbsp;&nbsp;&nbsp;&nbsp;The Molecular Recognition (MR) in living systems is a crucial elementary process for biomolecules to perform their functions as, for example, enzymes or ion channels. The MR process can be defined as a molecular process in which one or few guest molecules are bound in high probability at a particular site, a cleft or a cavity, of a host molecule in a particular orientation. The process is governed essentially by the two physicochemical properties: (1) difference in the thermodynamic stability (or free energy) between the bound and unbound states of host and guest molecules, and (2) structural fluctuation of molecules. In the dissertation, I propose a new theory to describe the molecular recognition process based on the statistical mechanics of molecular liquids.</br>&nbsp;&nbsp;&nbsp;&nbsp; The new theory of MR referred to as uu-3D-RISM is formulated in Chapter II, after a brief sketch of the three-dimensional reference interaction site model (3D-RISM) theory, a statistical mechanics theory of molecular liquids, on which the new theory of MR is based. The 3D-RISM theory itself has been applied successfully to a variety of MR problems in the last five years in Hirata’s group. I myself applied the theory to binding of small ligands, such as CO and O2, in myoglobin. (The study is presented in the following chapter.) However, the 3D-RISM equation had some technical problem when it is applied to a larger ligand typically used as a drug. The new theory overcomes the problem, and can be applied to larger organic molecules. </br>&nbsp;&nbsp;&nbsp;&nbsp;Both the 3D-RISM and uu-3D-RISM equations are derived from the molecular Ornstein-Zernike (MOZ) equation, the most fundamental equation to describe the density pair correlation of liquids, for a solute-solvent system in the infinite dilution by taking a statistical average over the orientation of solvent molecules. By solving combined the 3D-RISM with RISM equations, the latter providing the solvent structure in terms of the site-site density pair correlation functions, one can get the “solvation structure” or the solvent distributions around a solute. The high peak of the solvent distributions indicates that the solvent affinity of target protein or receptor at that point is high. Therefore, the MR can be realized by the theories in terms of the distribution of solvent or ligand just like in the X-ray crystallography. The method produces naturally all the solvation thermodynamics as well, including energy, entropy, free energy, and their derivatives such as the partial molar volume and compressibility. </br>&nbsp;&nbsp;&nbsp;&nbsp;In the all previous studies of MR due to the 3D-RISM theory, the receptor protein and ligand molecules were regarded as solute and solvent, respectively. In those cases, the MR process is analyzed in terms of solvent distribution around solute molecule, which is called as sol’u’te-sol’v’ent distribution function (uv-DF). However, it is still difficult technically to treating a large ligand molecule as solvent in terms of numerical convergence. Therefore, I propose a new approach to tackle the MR of large ligand molecules by protein based on the 3D-RISM and RISM theory. The strategy of the method is to regard a ligand molecule as solute which is immersed in solvent in the infinite dilution limit in addition to a receptor protein. The distribution of ligand molecule around a receptor protein is described by the sol’u’te-sol’u’te distribution function (uu-DF) instead of sol’u’te-sol’v’ent DF (uv-DF). In this sense, the new method is named uu-3D-RISM. Under the treatment of this method, interactions between ligand molecules are completely omitted, because the density of ligand molecule vanishes at the limit. Therefore, it is not necessary to solve the ligand-ligand RISM equation, most unstable equation, anymore. This assumption stabilizes the numerical solutions of a set of the 3D-RISM and RISM equations dramatically. </br>&nbsp;&nbsp;&nbsp;&nbsp;In Chapter III, the molecular recognition of small ligands to myoglobin is studied by using the original 3D-RISM theory. The Chapter consists of two sections. The first section treats the binding affinity of small ligands including O2, Xe, NO, CO, H2S, and H2O to myoglobin. Those ligands are known to show some physiological activities in living bodies, such as anesthetics, poisons or signal transducer. Although it is not entirely clear how the affinity of these ligands to cavities inside the myoglobin is related to the physiological activities, it is worthwhile to find out the factors to determine the selectivity of the ligands to the cavities to provide basic molecular information to the physiology. The affinity is evaluated in terms of the coordination number of the ligand molecules in cavities in the protein, or the “Xe site,” which can be obtained from the radial distribution of ligands inside the cavities. It was found that NO, CO, and H2S show greater affinity to the Xe-sits than O2 does, while the affinity of Xe is lower than that of O2.</br>&nbsp;&nbsp;&nbsp;&nbsp;The second section concerns the CO escaping pathway of myoglobin. The CO dissociating process occurs from heme to solvent through some specific cavity. The CO escaping pathway from myoglobin was discussed in terms of partial molar volume change along the pathway.</br>&nbsp;&nbsp;&nbsp;&nbsp; The results showed excellent agreement with those from the transient grating experiments carried out by Terazima and his coworker.</br>&nbsp;&nbsp;&nbsp;&nbsp;In Chapter IV, the new methodology, or uu-3D-RISM, described in the chapter II, is applied to two types of proteins, the structure of which can be available in the Brookhaven Protein Data Bank (PDB). </br>&nbsp;&nbsp;&nbsp;&nbsp;One is the odorant binding protein LUSH, which can form a complex with a series of short-chain n-alcohols, from Drosophila melanogaster. It clears a set of molecular interactions between the protein and the alcohol at a specific alcohol-binding site. In order to prove the robustness of the new method, both the original 3D-RISM and the new method is applied to this system. </br>&nbsp;&nbsp;&nbsp;&nbsp;The other example is Phospholipase A2 (PLA2) enzyme which can form the complex with 2-acetoxybenzoic acid, a compound well known as “aspirin.” Aspirin induces its anti-inflammatory effects through its specific binding to PLA2. PLA2 is potentially an important target for structure-based rational drug design. Aspirin is embedded in the hydrophobic environment and several important attractive interactions are formed with protein. Our calculation clearly shows that aspirin occupies a favorable place in the specific binding site of PLA2. </br>&nbsp;&nbsp;&nbsp;&nbsp;The results for the both proteins demonstrate that the new theory is a powerful tool to describe the molecular recognition process of biomolecules in living system.</br>","subitem_description_type":"Other"}]},"item_1_description_7":{"attribute_name":"学位記番号","attribute_value_mlt":[{"subitem_description":"総研大甲第1405号","subitem_description_type":"Other"}]},"item_1_select_14":{"attribute_name":"所蔵","attribute_value_mlt":[{"subitem_select_item":"有"}]},"item_1_select_8":{"attribute_name":"研究科","attribute_value_mlt":[{"subitem_select_item":"物理科学研究科"}]},"item_1_select_9":{"attribute_name":"専攻","attribute_value_mlt":[{"subitem_select_item":"08 機能分子科学専攻"}]},"item_1_text_10":{"attribute_name":"学位授与年度","attribute_value_mlt":[{"subitem_text_value":"2010"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"KIYOTA, Yasuomi","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"0","nameIdentifierScheme":"WEKO"}]}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2016-02-17"}],"displaytype":"simple","filename":"甲1405_要旨.pdf","filesize":[{"value":"295.8 kB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"要旨・審査要旨","url":"https://ir.soken.ac.jp/record/2460/files/甲1405_要旨.pdf"},"version_id":"f1fb9f71-7f3d-4b56-83bc-76e77181c3f7"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"thesis","resourceuri":"http://purl.org/coar/resource_type/c_46ec"}]},"item_title":"Molecular Recognition Process of Biological Molecules Studied with a Statistical Mechanics Theory","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Molecular Recognition Process of Biological Molecules Studied with a Statistical Mechanics Theory"},{"subitem_title":"Molecular Recognition Process of Biological Molecules Studied with a Statistical Mechanics Theory","subitem_title_language":"en"}]},"item_type_id":"1","owner":"21","path":["10"],"pubdate":{"attribute_name":"公開日","attribute_value":"2011-12-21"},"publish_date":"2011-12-21","publish_status":"0","recid":"2460","relation_version_is_last":true,"title":["Molecular Recognition Process of Biological Molecules Studied with a Statistical Mechanics Theory"],"weko_creator_id":"21","weko_shared_id":-1},"updated":"2023-06-20T15:51:10.650690+00:00"}