Shape factors in the binding of soft fluorescent nanoshuttles with target receptors

Amphiphilic nanoparticles are highly biocompatible frameworks widely used for shuttling hydrophobic molecules across hydrophilic cellular environments. Their use can also span applications focused on achieving a selective binding against a target receptor. However, the molecular factors leading to an optimal binding often remain a critical step to assess. Here we have evaluated through advanced sampling free-energy simulations, combined with electronic circular dichroism spectra predictions, the binding of an amphiphilic polyethylene glycol (PEG)-based nanoparticle incorporating folate monomers with human folate receptor alpha. It turns out from the free-energy predictions that the optimal binding is achieved when the receptor target and the ligand-mimicking nanoparticle have a comparable size and the shortest spacer length of the folate monomer. Furthermore, we calculated the ECD spectrum of the folate monomer binding the target receptor, as well as that of the binding pocket of the receptor. Noteworthy, only when the optimal binding is achieved, the two ECD spectra closely match each other. Shape factors control the binding efficacy of nanoparticles with target receptors.