# Ion-Ion Interactions and the Reverse Hofmeister Effect

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $372,402

## Abstract

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.

## Key facts

- **NIH application ID:** 9944588
- **Project number:** 5R01GM125690-03
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** BRUCE C GIBB
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,402
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944588

## Citation

> US National Institutes of Health, RePORTER application 9944588, Ion-Ion Interactions and the Reverse Hofmeister Effect (5R01GM125690-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9944588. Licensed CC0.

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