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Thermodynamic Analysis of Protein-Ligand interactions

蛋白质-配体相互作用的热力学分析

基本信息

批准号：
10557216
负责人：
KOBAYASHI Yuji
金额：
$ 5.12万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557216/
关键词：
Protein-Ligand intenaction thermodynamics volumetric study intrinsic volume intrinsic compriessibility 偏比容

项目摘要

A major biological function of many proteins is the binding of small molecules. For examples, enzymes bind substrates and effector molecules, and transport proteins such as hemoglobin or storage proteins such as myoglobin bind oxygen. Almost all biological functions involve the interactions of those small molecules that serve as metabolites, regulators, and signals with the specific surfaces of the proteins that carry out cellular processes. For this reason, an understanding of the mechanisms of such interactions is essential to a comprehension of biological process at the molecular level. In most cases, such binding involves the formation of some kind of noncovalent bond between the small molecules called as ligand and some specific region on or near the surface of the protein called as the binding site. The protein-lgand complexes are in thermodynamic equilibrium with their dissociated components, and in many cases it is possible to measure the thermodynamic parameters for these reac … More tions.Fundamental thermodynamic relationships reveal that volumetric studies on molecules of interest can yield useful new information. The intrinsic volume, Vm, (the geometric volume of a solute not accessible to surrounding solvent molecules) and the intrinsic compressibility, Km, (compressibility of the solvent-inaccessible protein core) of a protein-ligand complex reflect the intrinsic packing of the constituent and are detemined by intermolecular interactions within the solvent-inaccessible protein interior. Consequently, any changes in protein structure induced by ligand binding should be reflected in the values of Vm and Km.In this research project, the properties of protein-ligand complex as a function of solution conditions, including the role of solvation have been characterized by volumetric studies. Until recently, such studies on biologically interesting molecules have been limited because of the lack of readily available instrumentation with the requisite sensitivity. We have improved the instruments and constructed a highly sensitive, small-volume densimetric, acoustic and high-pressure spectroscopic instrumentation which enabled biological molecules to be subjected to a wide range of volumetric studies. Using these instruments, we have obtained unique insights into the molecular origins of the intermolecular recognition events that modulate biomolecular processes. Less

许多蛋白质的一个主要生物学功能是结合小分子。例如，酶结合底物和效应器分子，运输蛋白如血红蛋白或储存蛋白如肌红蛋白结合氧。几乎所有的生物功能都涉及那些作为代谢物、调节剂和信号的小分子与执行细胞过程的蛋白质的特定表面的相互作用。因此，了解这种相互作用的机制对于在分子水平上理解生物过程是至关重要的。在大多数情况下，这种结合涉及到在称为配基的小分子和蛋白质表面或附近称为结合位置的特定区域之间形成某种非共价键。蛋白质-…复合体与它们的解离组分处于热力学平衡状态，在许多情况下，可以测量这些反应物的热力学参数。基础热力学关系表明，对感兴趣分子的体积研究可以产生有用的新信息。蛋白质-配基复合体的固有体积Vm(周围溶剂分子无法接触到的溶质的几何体积)和固有可压缩性Km(溶剂不可接触的蛋白质核心的可压缩性)反映了组分的内在堆积，并由溶剂不可接触的蛋白质内部的分子间相互作用决定。因此，配体结合引起的蛋白质结构的任何变化都应该反映在Vm和Km的值上。在本研究项目中，通过体积研究表征了蛋白质-配体复合体的性质作为溶液条件的函数，包括溶剂化的作用。直到最近，由于缺乏现成的仪器和必要的灵敏度，对生物学上有趣的分子的这种研究一直是有限的。我们改进了仪器，构建了高灵敏度、小体积密度、声学和高压光谱分析仪器，使生物分子能够进行广泛的体积研究。使用这些仪器，我们对调节生物分子过程的分子间识别事件的分子起源获得了独特的见解。较少