title: Computational insights on the possibility of tri-coordinated cisplatinated adducts with protein models.
abstract: 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.
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ortega-Carrasco
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Cossío
authors.forename: Agustí
authors.initials: A
authors.lastname: Lledós
authors.forename: Jean-Didier
authors.initials: JD
authors.lastname: Maréchal
mesh_terms: D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry*; D003198:Computer Simulation; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D011506:Proteins; C034297:diamminediaqua platinum(II); D009113:Muramidase; D002945:Cisplatin