MDN: A Web Portal for Network Analysis of Molecular Dynamics Simulations

Abstract

We introduce a web portal that employs network theory for the analysis of trajectories from molecular dynamics simulations. Users can create protein energy networks following methodology previously introduced by our group, and can identify residues that are important for signal propagation, as well as measure the efficiency of signal propagation by calculating the network coupling. This tool, called MDN, was used to characterize signal propagation in Escherichia coli heat-shock protein 70-kDa. Two variants of this protein experimentally shown to be allosterically active exhibit higher network coupling relative to that of two inactive variants. In addition, calculations of partial coupling suggest that this quantity could be used as part of the criteria to determine pocket druggability in drug discovery studies.

Figure 1

Short system summary after completed file upload for the DnaK test case.

Figure 2

Network setup for the DnaK test case. (A) Network construction for group Protein (600 nodes). (B) Network construction for group SBD (108 nodes).

Figure 3

Selecting nodes for pathway calculation for the DnaK test case. A) Example showing group choice that leads to all pathways for the group called Protein being calculated. B) Example showing choice that leads to pathways between two non-overlapping groups (SBD and NBD) being calculated.

Figure 4

DnaK structure (PDB 2KHO). (A) Visualization of the three domains: the NBD (magenta), the SBD (green), and the C-terminal domain (yellow). The NBD-SBD linker is colored in black. Residues K70, D388, and D393 are shown as spheres. (B) Visualization of the five pockets identified by Rodina and co-workers (40). Residues lining the pockets are represented as spheres colored according to the color code. To see this figure in color, go online.

Figure 5

Maps of energetic coupling for DnaK WT and for mutants experimentally found to be allosterically active (D388R) or inactive (D393R and K70E). Each amino acid in the NBD is colored according to the energetic coupling calculated between that amino acid and all amino acids forming the SBD (green). To see this figure in color, go online.