SI-PPC-induced modulation of heparin/heparanase binding affinity: a steered molecular dynamics approach

Abstract

We report a steered molecular dynamics (SMD) investigation into how substitution-inert polynuclear platinum complexes (SI-PPCs) influence the binding affinity between heparan sulphate (HS) and the enzyme heparanase. By simulating the forced dissociation of HS from the enzyme's active site, we demonstrate that the presence of cationic SI-PPCs substantially reduces the work required to pull the HS substrate away. Compared to the unmodified system, this work decreases by an average of 35.6% in the presence of these platinum complexes, highlighting their “metalloshielding” effect. Detailed analysis of hydrogen bonding and the formation of cyclic sulphate clamps and forks revealed that SI-PPCs stabilize the anionic HS moieties, effectively masking them from enzymatic cleavage. Among the complexes tested, those with greater charge and hydrogen-bonding capacity formed more stable noncovalent interactions. These findings provide mechanistic insight into the experimentally observed inhibition of HS-degrading enzymes by SI-PPCs and offer a pathway for the rational design of new agents to hinder tumour cell invasion and metastasis.