LAUSR

Design of pH-responsive monolayer-protected gold nanoparticles (AuNPs) that are mixed charged, with the ability to switch their net surface charge, based on the stimuli of environmental pH is a promising technique in nanomedicine. However, understanding of pH-responsive mixed charged AuNP behavior in terms of their stability and cellular interaction are still limited. In this work, we study the aggregation of pH-responsive AuNPs and their interaction with model lipid bilayers by adopting Martini coarse-grained (CG) molecular dynamics simulations. The surface of these AuNPs is decorated by both positively and negatively charged ligands. The AuNP is positively charged at low pH values due to protonation of negatively charged ligands. Its net charge is lowered at higher pH by increasing the ratio of deprotonated negatively charged ligands. We find that the AuNPs are severely aggregated at moderate pH value, where each AuNP has an overall neutral charge, whereas they are stable and dispersed at both low and high pH values. Further free energy analysis reveals that the energy barrier at a larger separation distance than the location of the hydrophobic driving force potential well, plays a key role that determines the stability of monolayer-protected AuNPs at different pH values. This energy barrier is dramatically decreased at moderate pH value, leading to severe aggregation of AuNPs. By investigating the interaction between AuNPs and model lipid bilayers, we find that all the AuNPs adhere onto the lipid bilayer, independent of the pH value. Moreover, the lipids present originally in the bilayer are extracted by the AuNPs through a process of protrusion and upward climbing. The extraction of lipids can cause dehydration and disruption of the bilayers when multiple AuNPs are adhered. Free energy analysis reveals that the penetration of AuNPs will induce a dramatic free energy increase because of deformation of the ligands with hydrophilic functional end groups. We have systematically studied the stability of pH-responsive AuNPs and their interactions with lipid bilayers by simulation, which might pave the way for the design of pH-responsive monolayer protected AuNPs for biomedical applications.