# Hierarchy of Hydrophobic and Electrostatic Interactions in DNA–Membrane Phase Selectivity

## TL;DR

This study explores how hydrophobic and electrostatic forces influence DNA's ability to selectively bind to different types of lipid membranes, offering a framework for designing DNA-membrane interfaces.

## Contribution

The paper introduces a design hierarchy for DNA–membrane phase selectivity based on hydrophobicity, multivalency, and ionic conditions.

## Key findings

- Hydrophobic anchor strength and identity determine DNA binding and phase selectivity.
- Multivalency enhances binding affinity while preserving selectivity for weak anchors.
- Electrostatic interactions stabilize DNA–lipid complexes but reduce specificity at high ion concentrations.

## Abstract

DNA–lipid interfaces are pivotal in synthetic
biology and
biomedicine, yet their design for phase-separated membranes remains
poorly understood. Here, we investigate how hydrophobic anchoring
and electrostatic forces govern DNA partitioning in liquid-ordered
(Lo) and liquid-disordered (Ld) lipid domains.
Using programmable DNA nanostructures functionalized with hydrophobic
anchors, we show that anchor hydrophobicity and chemical identity
dictate binding strength and phase selectivity, while multivalency
enhances affinity and preserves selective partitioning for weak anchors.
Electrostatic bridging stabilizes DNA–lipid complexes but compromises
specificity at high concentrations, whereas competitive monovalent
ions dynamically shift equilibria toward hydrophobicity-driven localization.
Dual-anchor constructs reveal hierarchical partitioning, where stronger
anchors dominate despite competing preferences and the effects of
multivalency. Balancing hydrophobic and electrostatic affinity is
key; we establish a design hierarchy in which hydrophobic anchors
control phase specificity, multivalency tunes binding strength, and
ionic conditions act as secondary modulators. This work provides a
roadmap for engineering responsive and phase-selective DNA–membrane
interfaces, with implications for drug delivery, synthetic biology,
and biomimetic DNA materials.