Physicochemical insights into the interaction of cationic peptides (KR12 and TAT _(47–57) ) with decavanadate: an integrated ITC and molecular dynamics study

This study provides a comprehensive physicochemical characterisation of the interactions between the decavanadate ([V₁₀O₂₈]^6-) and two model cationic peptides: the antimicrobial peptide KR12 (net charge +5) and the cell-penetrating peptide TAT_(47-57) (net charge +9). Isothermal titration calorimetry (ITC) revealed that both peptides form complexes with decavanadate of comparable thermodynamic stability (Δ<i>G</i> = -9.79 ± 0.10 kcal mol^-1 for KR12 and -10.24 ± 0.26 kcal mol^-1 for TAT_(47-57)). However, the overall thermodynamic stability of these complexes is governed by distinct thermodynamic patterns. The binding of TAT_(47-57), with its higher charge and greater flexibility, is characterised by a significantly more exothermic enthalpy change (Δ<i>H</i> = -15.50 ± 0.12 kcal mol^-1) compared to KR12 (Δ<i>H</i> = -10.01 ± 0.04 kcal mol^-1). A greater entropic penalty offsets the pronounced enthalpic gain for TAT_(47-57). In contrast, KR12 binding involves a more moderate enthalpy-entropy balance. These results highlight how variations in net charge and structural flexibility of the peptides can converge on similar binding affinities through fundamentally different thermodynamic mechanisms, primarily driven by electrostatic interactions. A comparative analysis with KR12 lipopeptides showed that fatty acid conjugation weakens affinity (KR12 > C12-KR12 > C14-KR12) by reducing conformational flexibility. MD simulations confirmed binding is governed by electrostatic interactions with key cationic residues in both peptides. CD spectroscopy revealed that neither peptide adopts a stable α-helix upon binding. These findings highlight the crucial interplay of electrostatics and entropy in peptide-polyoxovanadate interactions, establishing a basis for understanding their biological behaviour.