Blue moon ensemble simulation of aquation free energy profiles applied to mono and bifunctional platinum anticancer drugs

TL;DR

This study uses advanced DFT-MD simulations to compute aquation free energy profiles of platinum-based anticancer drugs, revealing similar activation energies and detailed solvation structures, enhancing understanding of their aqueous behavior.

Contribution

It introduces a novel simulation approach combining thermodynamic integration with explicit solvent modeling to analyze aquation mechanisms of platinum drugs.

Findings

Aquation free energies are similar across different platinum drugs.

Inverse hydration is a common feature in these systems.

Detailed microsolvation structures elucidate key aquation steps.

Abstract

Aquation free energy profiles of neutral cisplatin and cationic monofunctional derivatives, including triaminochloroplatinum(II) and cis-diammine(pyridine)chloroplatinum(II), were computed using state of the art thermodynamic integration, for which temperature and solvent were accounted for explicitly using density functional theory based canonical molecular dynamics (DFT-MD). For all the systems the "inverse-hydration" where the metal center acts as an acceptor of hydrogen bond has been observed. This has motivated to consider the inversely bonded solvent molecule in the definition of the reaction coordinate required to initiate the constrained DFT-MD trajectories. We found that there exists little difference in free enthalpies of activations, such that these platinum-based anticancer drugs are likely to behave the same way in aqueous media. Detailed analysis of the microsolvation structure of the square-planar complexes, along with the key steps of the aquation mechanism are discussed.