Computational insights on the possibility of tri-coordinated cisplatinated adducts with protein models

In the organism, cisplatin binds to numerous proteins. These interactions can ultimately lead to the emergence of resistance and side effects. Little is known on these recognition processes with only few crystallographic structures of cisplatinated proteins released so far. Some of them, like the monoadduct of cisplatin with the hen egg white lysozyme, display unexpected structural features. Instead of the usual square planar configuration of the metal, an apparent T-shaped geometry is observed. This tri-coordinated structure could be a consequence of some crystallographic limitations. However, the increasing reports of tri-coordinated Pt(II) organometallic complexes questions whether it could also have some physiological relevance. Here, we present a computational study allying pure quantum mechanical and hybrid quantum mechanical/molecular mechanics methodologies to shed light on this particular question. Calculations on monoadducts of cis-diamminediaquo-platinum(II) with protein models show that square planar geometries are, as expected, the most stable ones. Dehydrations leading to trigonal geometries have Gibbs energies ranging from 8 to 31 kcal/mol and indicate that some of them may be possible in a proteic environment. Nonetheless, we also observed that such conditions are not afforded in the hen egg white lysozyme adduct.

The interaction of cisplatin with proteins is a key event in its side effect profile. Recent crystallographic structures have showed apparent T-shaped geometries in the binding of cisplatin to different receptors. This study investigates by computational means the structural features and energetic accessibility of tri-coordinated geometries for cisplatin–protein adducts.Figure optionsDownload as PowerPoint slideHighlights
► Gas phase tri-coordinated complexes of cisplatin bound to amino acids were calculated.
► No second sphere interaction is needed to stabilize these structures.
► Dehydrations are not spontaneous but in some cases their Gibbs energy are small.
► T-shaped geometries are more likely to occur in solvent exposed environments.
► A T-shaped of cisplatin with the hen egg white lysozyme is not supported.