Pressure-induced p <i>K</i> a variations influence conformations of pH-sensitive polymers

Abstract

Conformations of aqueous macromolecules depend on a delicate balance of hydrophobic, electrostatic, and hydrogen-bonding interactions, all of which are influenced by environmental factors such as pressure and pH. Understanding how these factors modulate structural stability is critical for both biological and material science applications. Here, we use constant-pH molecular dynamics simulations to investigate the pressure response of a short, pH-sensitive polymer in explicit solvent. Our results reveal that increasing pressure unfolds both neutral and charged polymers, but the degree of unfolding is markedly reduced when the polymer carries a charge, demonstrating the coupling of pressure and charge regulation. At pH = pKa, we observe a pressure-dependent transition from neutral-like behavior at low pressure to charged-like behavior at high pressure, a signature of pressure-induced pKa shifts. Additionally, pressure-induced unfolding is enhanced at this pH. Extending our study to a model polyampholyte with one acidic and one basic monomer, we find clear evidence of non-additive acid–base coupling that stabilizes collapsed states at low pressure, as well as pressure-induced salt-bridge denaturation at high pressure. This behavior reveals a competition between electrostatic stabilization and pressure-driven hydration effects. These findings shed some light on the pressure-modulated macromolecular behavior of charged and neutral polymers and provide insights relevant to both synthetic polymers and pressure-adapted biological systems.