Dual-mode modelling of solid-phase peptide synthesis on SiO 2

Solid-phase peptide synthesis (SPPS) assembles peptide sequences through stepwise coupling of protected amino acids. Its scalability and capacity for automation make it a method of choice for synthesising peptide-based pharmaceuticals. Industrial SPPS requires super-stoichiometric reagent quantities and large solvent volumes to ensure reaction completion; in-situ monitoring of reaction progress offers a direct path to reduce this consumption by terminating each step once complete, aligning peptide manufacturing with more responsible resource and solvent use, and enables interrogation of reaction kinetics, side reactions, and yield. In this work, we encode each interface-tethered SPPS reaction intermediate on SiO2 as a Simplified Molecular-Input Line-Entry System (SMILES) string. From this single SMILES encoding, we perform two parallel calculations: i) prediction of site-specific pK values, which we combine with electrostatic modelling (site-binding and Gouy–Chapman–Stern formalism) to derive the pH-dependent surface potential ψ0(pH), relevant for charge-based field-effect transistor (FET) interrogation, and ii) computation of molar refractivity (MR) via atomic-contribution methods, used here as an optical surrogate for surface plasmon resonance (SPR) response. We apply this framework to a representative four-step SPPS pathway on APTES-functionalised SiO2. Joint charge- and refractive-index-based interrogation distinguishes all protected and deprotected intermediates in the pathway, showing that dual-mode FET+SPR monitoring can identify reaction completion at each synthesis step. As an initial step toward height-resolved modelling, we generate energy-minimised three-dimensional conformations of reaction intermediates and assign heights to titratable and polarisable groups relative to the oxide surface, providing a foundation for future depth-weighted electrostatic and optical calculations. This framework establishes a direct connection between molecular structure, interfacial chemistry, and dual-mode electrical and optical observables, and provides a basis for in-situ monitoring of SPPS reaction completion.