Pressure-induced pKa shifts influence conformations of pH-sensitive polymers

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 (cpHMD) 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, while the response to pressure is dampened when the polymer is charged. At pH = pKa, we observe a pressure-dependent transition from neutral-like behavior at low pressure to charged-like behavior at high pressure, suggesting pressure-induced pKa shifts. Extending our study to a model polyampholyte with one acidic and one basic monomer, we observe that the acid and the base are coupled, leading to stabilization of collapsed states. We also observe pressure-induced salt bridge denaturation, suggesting that this stabilization due to acid-base coupling is not sufficient to protect against unfolding due to increasing pressure. 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.