In silico docking, molecular dynamics and binding energy insights into the bolinaquinone-clathrin terminal domain binding site - PubMed (original) (raw)

In silico docking, molecular dynamics and binding energy insights into the bolinaquinone-clathrin terminal domain binding site

Mohammed K Abdel-Hamid et al. Molecules. 2014.

Abstract

Clathrin-mediated endocytosis (CME) is a process that regulates selective internalization of important cellular cargo using clathrin-coated vesicles. Perturbation of this process has been linked to many diseases including cancer and neurodegenerative conditions. Chemical proteomics identified the marine metabolite, 2-hydroxy-5-methoxy-3-(((1S,4aS,8aS)-1,4a,5-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-2-yl)methyl)cyclohexa- 2,5-diene-1,4-dione (bolinaquinone) as a clathrin inhibitor. While being an attractive medicinal chemistry target, the lack of data about bolinaquinone's mode of binding to the clathrin enzyme represents a major limitation for its structural optimization. We have used a molecular modeling approach to rationalize the observed activity of bolinaquinone and to predict its mode of binding with the clathrin terminal domain (CTD). The applied protocol started by global rigid-protein docking followed by flexible docking, molecular dynamics and linear interaction energy calculations. The results revealed the potential of bolinaquinone to interact with various pockets within the CTD, including the clathrin-box binding site. The results also highlight the importance of electrostatic contacts over van der Waals interactions for proper binding between bolinaquinone and its possible binding sites. This study provides a novel model that has the potential to allow rapid elaboration of bolinaquinone analogues as a new class of clathrin inhibitors.

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Conflict of interest statement

The authors declare the following competing financial interest(s): We have entered into a commercial agreement with Abcam Biochemicals (Bristol, UK) for the supply of our clathrin inhibitors. This includes some of the compounds listed in this paper. Pitstop® is a registered trademark of Children’s Medical Research Institute (Sydney, Australia) and Newcastle Innovation, Ltd. (Newcastle, Australia)

Figures

Figure 1

Figure 1

Chemical structure of the marine metabolite bolinaquinone (1).

Figure 2

Figure 2

(A) Ribbon representation of a top view of the CTD (2XZG). The positioning of each of the seven β-stranded blades is indicated by the numbers 1-7. The predicted binding clusters for the docked 1 poses are rendered in stick representation and are color coded (non-carbon atoms) with formula image (clathrin-box binding site), formula image (site 1), formula image (site 2) and formula image (site 3). (B) Same representation as in A rotated 90° inward, indicating potential 1 binding sites. (C) Bar graph representation of the number of 1 poses in each binding site cluster shown in A and B. The bar colors correspond to the binding sites and 1-clusters identified in A and B.

Figure 3

Figure 3

Molecular dynamics trajectory plots correlating RMSD deviation from the initial 1-CTD protein Cα atoms (blue) and 1 heavy atoms (red) coordinates over a simulation time of 20 ns. (A) Trajectory plot output for binding site 1; (B) Trajectory plot output for binding site 2; (C) Trajectory plot output for binding site 3; and (D) Trajectory plot output for the clathrin-box binding site. Stable complexes are shown in A, B and D while C shows distortion of the complex structure just after 15 ns.

Figure 4

Figure 4

The average energy minimized structure of the molecular dynamics simulated 1 (grey stick representation) bound at the potential binding site 1 of the CTD (only relevant residues are shown as line representation and water molecules are shown as red spheres). Potential hydrogen bonding between 1 and the binding site are shown as black dashed lines.

Figure 5

Figure 5

Electrostatics maps (Hydrophobic; green, Hydrogen bond acceptor; red and Hydrogen bond donor; blue) for 1 (stick representation) bound at the proposed CTD binding site.

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