ABSTRACT
In this study, the interaction of cisplatin (1) and two potential antitumoral Pt(II) complexes (2 and 3) with a model DMPC bilayer was investigated by multinuclear NMR spectroscopy and MD simulations in order to understand its implication for the different antitumoral properties shown by the three complexes. In particular, (31)P, (13)C and (2)H solid state NMR experiments were performed to obtain information on the phase structure, phase transitions and structural and dynamic changes in the phospholipid bilayer upon interaction with the platinum complexes. On the other hand, MD calculations yielded free energy profiles for the different complexes across the bilayer; the results were analysed to obtain MD predictions on complex distribution with respect to the bilayer, as well as to establish their effects on the conformational equilibrium of the DMPC acyl chains. The combination of NMR and MD approaches highlighted that, whereas the more hydrophilic cisplatin tends to remain in the polar head group region causing a decrease in flexibility of the bilayer, the two new complexes enter into the bilayer. In particular, complex 2 is preferentially located relatively close to the surface, only slightly affecting the bilayer structure and mobility, while complex 3 penetrates more deeply, strongly perturbing the bilayer and giving rise to lateral phase separation.
Subject(s)
Antineoplastic Agents/metabolism , Cell Membrane/chemistry , Cisplatin/chemistry , Lipid Bilayers/chemistry , Molecular Dynamics Simulation , Organoplatinum Compounds/chemistry , Antineoplastic Agents/chemistry , Cell Membrane/metabolism , Cisplatin/metabolism , Dimyristoylphosphatidylcholine/chemistry , Lipid Bilayers/metabolism , Magnetic Resonance Spectroscopy , Molecular Conformation , Organoplatinum Compounds/metabolismABSTRACT
The National Institute of Health (NIH) peer review process for research grant applications is one of the largest and most respected systems of its kind in the world. Recently, however, the distribution of raw priority scores voted by NIH study sections has been skewed, and the rating behavior of individual review groups has been quite variable. These phenomena have made funding decisions more difficult. To achieve greater uniformity of rating behavior and a broader description of scores, an experiment was conducted involving 24 study sections. Standard adjectival descriptors and standard rating scales were used. On a random basis, half of the study sections were instructed to vote in units of 0.1 while the other half used an interval of 0.5. The results of this study have now been translated into standard practice at NIH.