Zwitterionic Polymer Nanodiscs for Low pH Buffer Compatibility
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Solution Overview
Problem
Traditional styrene-maleic acid lipid particles (SMALPs) are limited by incompatibility with low pH solutions and polyvalent cations, restricting their use in physiological conditions, particularly in environments with low pH and the presence of cations like MgCl2 and CaCl2.
Innovation Solution
Development of polymer-encased nanodiscs with styrene-maleic acid derivative repeating units that carry zero or nearly zero net negative charge, or zwitterionic styrene-maleic acid (zSMA) units, which are compatible with polyvalent cations and low pH conditions, allowing for improved buffer compatibility and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If traditional styrene-maleic acid copolymers are used to form SMALPs, then membrane proteins can be solubilized without detergent, but the SMALPs are incompatible with low pH solutions and polyvalent cations
Solution Approach 1:
The patent modifies the chemical parameters of the styrene-maleic acid copolymer by replacing the carboxylic acid groups with zwitterionic groups (such as sulfonate and quaternary ammonium groups). This parameter change transforms the polymer from being anionic and pH-sensitive to being zwitterionic and pH-stable, enabling compatibility with both low pH solutions and polyvalent cations while maintaining the ability to solubilize membrane proteins without detergent
Solution Approach 2:
The invention creates a composite polymer structure combining hydrophobic styrene groups with zwitterionic maleic acid derivative groups. This composite material approach allows the polymer to maintain amphipathic properties for membrane interaction while the zwitterionic components provide buffer compatibility, resolving the contradiction between ease of manufacture and adaptability
2Ease of manufacture
If traditional styrene-maleic acid copolymers are used, then nanodiscs can be formed with native lipids, but stability is compromised in physiological conditions with polyvalent cations and low pH
Solution Approach 1:
The patent changes the charge parameter of the copolymer from anionic to zwitterionic, which eliminates the electrostatic interaction problems with polyvalent cations that cause precipitation. The zwitterionic structure maintains stability across a wide pH range (including physiological pH and low pH conditions) while preserving the ability to form nanodiscs with native lipids, thus improving reliability without sacrificing ease of manufacture
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The new nanodiscs maintain stability and functionality in a wide range of pH conditions, including those below 5, and in the presence of polyvalent ions, enabling studies of membrane proteins that require these conditions, such as acidification-induced rhodopsin spectral shifts and ATPase activity.
Implementation Method 1
hydrolyzed alternating copolymers of maleic anhydride (anionic, hydrophilic in its hydrolyzed maleic acid form) and either styrene or an alkyl vinyl ether (hydrophobic) to associate with phospholipids to form flattened disk-like molecular assemblies
Implementation Method 2
polymer comprising zwitterionic styrene-maleic acid (zSMA) repeating units wherein the distribution of styrene and maleic acid derivative repeating units is random, and the zSMA is compatible with at least one of polyvalent cations, MgCl2, CaCl2, or pH
Data Source
AI summary
The present invention includes compositions, methods, and methods of making and using a polymer-encased nanodisc comprising: one or more integral membrane proteins in a lipid layer; and a polymer comprising zwitterionic styrene-maleic acid derivative repeating units that carry zero or nearly zero negative charge, and the polymer-encased nanodiscs.