Multi-scale simulation framework for understanding pH-controlled reversible self-assembly of SiO₂ nanoparticles with a bifunctional solid-binding protein

Solid-binding peptides provide remarkable opportunities for controlling hierarchical material assembly, but much remains to be learned about the fundamental mechanisms. Here, we use a bifunctional solid-binding protein containing two genetically engineered silica-binding peptides Car9 on opposite sides of a sfGFP protein scaffold to show that with a molar ratio of protein to silica nanoparticle (SiNP) of 5:1, aggregates formed at a pH of 7.5 can be repeatedly dissociated and reformed through cycles of pH between 7.5 and 8.5. We develop a multi-scale simulation framework to link the underlying molecular-scale features of the protein/SiNP interface with experimental observations, with the goal to predict aggregation pathways and kinetics. Interparticle interactions are calculated using atomistic molecular dynamics simulation and colloidal theory, based on which we construct coarse-grained (CG) rigid body simulations to obtain characteristic timescale for forming an aggregate of ~10² nm. We then bridge CG results with experiments using Smoluchowski theory for Brownian aggregation. We successfully simulate a pH-mediated reversible assembly that reproduces experimental results and identify crucial parameters that tune pathways and kinetics.