Ion-Ion Interactions and the Reverse Hofmeister Effect

离子-离子相互作用和逆霍夫迈斯特效应

基本信息

批准号：
10202645
负责人：
BRUCE C GIBB
金额：
$ 37.24万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202645
关键词：
Address Affect Affinity Ammonium Amyloid Anions Binding Binding Sites Biological Calorimetry Cations Charge Chlorides Complex Computer Assisted Crystallization Deposition Differential Scanning Calorimetry Disease Drug Industry Equilibrium Event Fresh Water Glean Goals Health Human Ions Knowledge Laws Lead Life Ligands Link Maps Modeling Molecular Nature Organic Chemistry Pathway interactions Perchlorates Personal Satisfaction Pharmacologic Substance Plant Roots Play Precipitation Prion Diseases Property Proteins Research Roentgen Rays Role Salts Science Scientist Sodium Chloride Solubility Solvents Spectrum Analysis Structure Surface Tension Thermodynamics Thrombosis Titrations Water Work X-Ray Crystallography biological systems design drug discovery experimental study improved in silico light scattering models and simulation molecular dynamics physical model protein aggregation protein folding response screening simulation small molecule solute

项目摘要

Project Summary Although the properties of dissolved organic solutes and salts have been studied for over 130 years, we know little of the laws governing how they interact. Consider for example the fact that NaI can lead to an increase in the solubility of a protein (the Hofmeister Effect) or bring about a decrease in solubility and lead to precipitation of a protein (the Reverse Hofmeister Effect, RHE). This application concerns the latter. Our understanding of the molecular interactions behind the RHE is limited. Indeed, it is only in the last decade that it has been confirmed that the key non-covalent interactions are those between the anion of the salt and positively charged groups on the solute. Beyond this, details are sparse: We know little about the magnitude of such interactions and whether they are dominated by Coulombic or dispersion interactions; we know little about the existence of specific ion-pairs that might dominate the precipitation of a solute; and we know little about the mechanisms of the aggregation and precipitation pathway(s). To develop an understanding of these we outline: 1) studies with model hosts designed to probe ion-ion pairing structurally and thermodynamically, and hence reveal details of how these lead to aggregation and precipitation; 2) molecular dynamics (MD) simulations designed to reveal atomistic details of these ion pairs, and the role water plays in modulating their thermodynamics of interaction, and; 3) studies with proteins that, building on our understanding of model hosts and MD simulations, will begin to systematically qualify and quantify how the RHE is manifest in proteins, and the specific ion-ion interactions behind this phenomenon. These studies will address the following scientific questions: · What are the specific ion-ion interactions pertinent to the RHE? · What are the specific structural features and thermodynamics of these ion-ion interactions? · Are there qualitative and quantitative links between the nature of ion pairing and the aggregation and precipitation of small molecules? · Do anion-protein interactions influence the structure, stability, and aggregation of proteins in specific, determinable ways? · Can the RHE in proteins be used as a signature to characterize/identify proteins? · Can the RHE in proteins be attributed to specific anion-protein interactions? Answering these questions will improve our understanding of the solubility of small molecules common to the pharmaceutical industry, and lead to a clearer picture of the often bewildering and contradictory RHE in proteins. This latter point is not only key to determining new ways to purify and crystallize proteins, but is also crucial to understanding the irreversible deposition of proteins in prion diseases and thrombosis.

项目摘要尽管溶解的有机溶剂和沙拉的特性已经研究了130多年，但我们几乎不了解管理如何互动的法律。例如，考虑NAI可以导致的事实增加蛋白质的可溶性形式（hofmeister效应）或可溶性形式下降并导致蛋白质的沉淀（反向Hofmeister效应，RHE）。该应用程序涉及后者。我们对RHE背后的分子相互作用的理解是有限的。确实，这只是在最后已经确认关键非共价相互作用的十年是阴离子之间的相互作用盐和充电的盐和积极的基团。除此之外，细节很少：我们对这种相互作用的幅度以及它们是由库仑或色散相互作用所支配的；几乎了解可能主导可溶性降水的特定离子对的存在。还有我们对聚集和降水途径的机制知之甚少。开发一个对这些概述的理解：1）使用旨在探测离子离子配对的模型宿主的研究在热力学上，因此揭示了这些导致聚集和降水的细节； 2）分子动力学（MD）模拟，旨在揭示这些离子对的原子细节，并作用水。扮演调节其相互作用的热力学，并且； 3）研究基于我们的蛋白质了解模型主机和MD模拟，将开始系统地限定和量化 RHE体现在蛋白质中，以及这种现象背后的特定离子离子相互作用。这些研究将解决以下科学问题： ·与RHE有关的特定离子离子相互作用是什么？ ·这些离子离子相互作用的特定结构特征和热力学是什么？离子配对与聚合的性质之间是否存在定性和定量联系小分子的沉淀？是否会影响蛋白质特定的蛋白质的结构，稳定性和聚集可确定的方法？ ·蛋白质中的RHE可以用作表征/识别蛋白质的签名吗？ ·蛋白质中的RHE可以归因于特定的阴离子 - 蛋白质相互作用吗？回答这些问题将改善我们对小分子常见解决方案的理解到制药行业，并更清楚地了解了经常造成的危害和矛盾蛋白质。以后的一点不仅是确定净化和结晶蛋白质的新方法的关键，而且是对于了解蛋白质在prion疾病和血栓形成中的不可逆转沉积至关重要。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Buffer and Salt Effects in Aqueous Host-Guest Systems: Screening, Competitive Binding, or Both?

DOI：
10.1021/jacs.1c08457
发表时间：
2021-11-10
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Jordan JH;Ashbaugh HS;Mague JT;Gibb BC
通讯作者：
Gibb BC

Anion binding to ubiquitin and its relevance to the Hofmeister effects.

DOI：
10.1039/d0sc04245e
发表时间：
2020-11-04
期刊：
Chemical science
影响因子：
8.4
作者：
Yao W;Wang K;Wu A;Reed WF;Gibb BC
通讯作者：
Gibb BC

Bright G-Quadruplex Nanostructures Functionalized with Porphyrin Lanterns.

DOI：
10.1021/jacs.9b03250
发表时间：
2019-08-14
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Pathak P;Yao W;Hook KD;Vik R;Winnerdy FR;Brown JQ;Gibb BC;Pursell ZF;Phan AT;Jayawickramarajah J
通讯作者：
Jayawickramarajah J

Dynamic Light Scattering - an all-purpose guide for the supramolecular chemist.

动态光散射 - 超分子化学家的通用指南。