DOTAP: Structure, Hydration, and the Counterion Effect

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2023 Jan 27

PMID 36703558

Authors

Mihaela Mihailescu

David L Worcester

Christopher L Carroll

A Richard Chamberlin

Stephen H White

Affiliations

Soon will be listed here.

Abstract

The cationic lipid 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) is one of the original synthetic cationic lipids used for the liposomal transfection of oligonucleotides in gene therapy. The key structural element of DOTAP is its quaternary ammonium headgroup that is responsible for interactions with both nucleic acids and target cell membranes. Because these interactions are fundamental to the design of a major class of transfection lipids, it is important to understand the structure of DOTAP and how it interacts with halide counterions. Here, we use x-ray and neutron diffraction techniques to examine the structure of DOTAP and how chloride (Cl-) and iodide (I-) counterions alter the hydration properties of the DOTAP headgroup. A problem of particular interest is the poor solubility of DOTAP/I- in water solutions. Our results show that the poor solubility results from very tight binding of the I- counterion to the headgroup and the consequent expulsion of water. The structural principles we report here are important for assessing the suitability of DOTAP and its quaternary ammonium derivatives for transfection.

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