Assessing the Stabilization of P-Glycoprotein’s Nucleotide- Binding Domains by the Linker, Using Molecular Dynamics

This paper focuses on the importance of the intermediate linker sequence for the stabilization of the cytoplasmic portion of murine P-glycoprotein, an ABC transporter involved in Multidrug Resistance (MDR) in cancer. Three putative protein-protein interaction areas were predicted to exist, two of them next to the C-terminal nucleotide-binding domain (NBD2) and the third one next to the inner leaflet interface of the lipid bilayer. These contact spots were confirmed by detailed contact maps from structures obtained before and after a 100 ns molecular dynamics production run, allowing a more thorough characterization of the type and number of residues involved in protein-protein contacts. It was found that these contact surfaces are located next to several highly conserved motifs of ABC transporters, serving as anchor points and assisting the linker’s ‘damper’ function.

Ricardo J. Ferreira [a],  Maria-José U. Ferreira [a], and Daniel J. V. A. dos Santos*[a, b]

[a] R. J. Ferreira, M.-J. U. Ferreira, D. J. V. A. dos Santos Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Medicinal Chemistry Av. Prof. Gama Pinto, Lisbon, Portugal

[b] D. J. V. A. dos Santos Faculty of Sciences, University of Porto REQUIMTE, Department of Chemistry and Biochemistry, Porto, Portugal


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