Modeling Framework for Solid-Phase Peptide Synthesis on SiO2

Solid-phase peptide synthesis (SPPS) allows for the sequential assembly of diverse peptide sequences. Alongside its scalability and capacity for automation, this makes it the method of choice for the synthesis of peptide-based pharmaceuticals. SPPS reaction pathways, however, suffer from a negative environmental footprint due to the super-stoichiometric quantities of reagents and high solvent use required to ensure reaction completion. In this paper, we propose the use of charge-based measurements as a complement to optical methods for measuring reaction completion. We extend the capabilities of our hybrid modeling framework to a representative four-step SPPS pathway on SiO2, showing each reaction intermediate, its molecular encoding, and the resulting modeled surface potential (ψ0). We show that the simulated ψ0(pH) plots are separable for three of the four key reaction steps in the representative pathway, indicating that charge-based measurements may help verify protection/deprotection steps.