Self-assembling peptides that respond to environmental stimulus, particularly pH fluctuations, are gaining significant attention for their potential use in a wide range of biomedical and biotechnological applications. These stimuli-responsive materials can adapt to varying pH conditions, which is crucial in systems such as drug delivery, biosensing, and tissue engineering. However, the design of pH-sensitive peptide assemblies has been limited by the lack of naturally occurring amino acids that exhibit the required pH responsiveness within the relevant biological range. To address this, we have developed a novel strategy that incorporates non-natural amino acids with ionizable side chains into peptide assemblies. These amino acids, specifically designed with tertiary amine groups, undergo pH-dependent ionization, allowing for the fine-tuning of the peptide’s behavior in response to environmental pH changes. Our experimental and computational results show that these ionizable residues integrate smoothly into the peptide structure, influencing the assembly's stability and disassembly at specific pH thresholds. Additionally, the incorporation of these non-natural amino acids enhances the peptides' functionality, such as their ability to disrupt bacterial membranes at acidic pH, offering potential applications in antimicrobial therapies. This new approach to designing pH-responsive peptide materials provides enhanced control over their properties, opening the door for their use in advanced drug delivery systems, sensors, and other bio-tech applications.
