Unveiling the Bio-Interface via Spectroscopic and Computational Studies of (Propyl-3-ol/butyl-4-ol)triphenyltin(IV) Compound Binding to Human Serum Transferrin

Two structurally tunable (propyl-3-ol)triphenyltin(IV) (Ph3SnL1) and (butyl-4-ol)triphenyltin(IV) (Ph3SnL2) compounds were investigated at the human serum transferrin (Tf) molecular interface to resolve how ligand architecture and protein metallation modulate organotin(IV) biocompound stability and lobe-selective binding. Steady-state fluorescence spectroscopy revealed efficient quenching of native Tf emission (λex = 280 nm, 296–310 K, pH 7.4) without significant spectral displacement, indicating the predominant formation of non-fluorescent ground-state complexes. Calculated bimolecular quenching constants (Kq ~1012 M−1 s−1) exceeded the diffusion-controlled aqueous limit, ruling out a collisional dynamic quenching mechanism and confirming static complexation as the principal origin of fluorescence suppression. Double-log binding analysis revealed moderate affinity (Ka ~102–103 M−1) and an approximately single dominant binding event per protein (n ≈ 0.65–0.90). Temperature-dependent van’t Hoff evaluation yielded positive ΔH° and ΔS° values, supporting a spontaneous, entropy-favored association process largely governed by hydrophobic and dispersion-type contributions, consistent with lipophilic organotin(IV) scaffold accommodation. Iron (Fe3+) loading of Tf markedly enhanced ligand engagement, especially for Ph3SnL1, evidencing that metallation-induced lobe closure reshapes pocket accessibility and local polarity relevant for organotin(IV) binding presentation rather than simply strengthening empirical docking scores. Molecular docking localized the most stable Ph3SnL2 poses in the sterically confined, rigid C-lobe, while Ph3SnL1 preferentially penetrated the more adaptive N-lobe. ONIOM QM/MM refinement of docking poses confirmed strong interfacial stabilization (ΔEint ≈ –38 to –62 kcal mol−1) and clarified charge–packing interplay without invoking frontier orbital analysis. The results map multiscale structure–interaction relationships defining lobe preference and complex stability at the transferrin interface.