On the Dynamics of Noncovalent Interactions Modulating Passive Diffusion of Cisplatin Across a Human Breast Cancer Cell Membrane: An amIGM + GLED View.

Passive permeation across biological membranes is governed by a delicate balance of transient noncovalent interactions that are difficult to resolve experimentally or through conventional molecular dynamics (MD) analyses alone. Here, we present a perspective on the integration of the averaged modified independent gradient model (amIGM) based on promolecular density approximation and the graphic representation of the local electron energy density (GLED) with classical MD simulations to investigate the passive translocation of the cisplatin (cisPt) anticancer drug across a model membrane representative of the lipid composition of breast cancer cells. This multiscale framework combines atomistic sampling with real-space descriptors, enabling the dynamic characterization of hydrogen bonding, dispersion forces, steric effects, and local electronic stabilization trends along the permeation pathway. As a proof of concept, we analyze the supramolecular nanosolvation environment of cisPt at finite temperature in two representative states: bulk aqueous solution and membrane center, corresponding to the maximum of the potential of mean force (+16 kcal mol-1). The combined amIGM/GLED approach reveals how the nature and spatial distribution of drug-water interactions evolve in response to the local membrane environment, providing mechanistic insight into the electronic and supramolecular factors that shape the free-energy landscape of passive permeation.