1st International and 10th National Iranian Conference on Bioinformatics
Home Accepted Papers
α-Glucosidase Un-Competitive Inhibition investigation via Residual Interaction Network, and Free Energy Landscapes: 0.5 μs Molecular Dynamics Simulations
Paper ID : 1389-ICB10
Authors:
Zahra Moosavi-Movahedi1, Mohammad Hossein Hossein Karimi Jafari2, Najmeh Salehi *3
1Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran,Tehran, Iran
2Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
3School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
Abstract:
Residual Interaction Network (RIN) analyses combined with molecular dynamics (MD) simulations have shown to be a powerful tool for the analysis of protein conformational dynamics, that plays a key role in the allosteric mechanism of enzymes. Here, with the coherence between RIN analysis and Free Energy Landscapes (FEL), two 250 ns trajectories are compared, which were created by MD simulations on free and xanthene derivatives bound of α-glucosidase. The use of two-dimensional principal component analysis (PCA) on cartesian coordinates of MD trajectories, leads to the discovery four basins in the conformational landscape of α-glucosidase and its complex to identify the representative of their sub-states. By integrating the networks of each basin conformations, and creating the mean network for each one, four intermediate networks of α-glucosidase were created. We also utilize the Girvan-Newman algorithm to detect communities and its interactions as a structural organization in α-glucosidase. The role of residues with large variations in the centrality values were examined on the pathways between the active site and distant allosteric site. Also, the hotspot residues distal from the active site, and residues with significant dynamical changes upon ligand-binding, and their communities are identified. So, the structure of α-glucosidase is well organized with different communities acting different roles in the ligand binding and allosteric un-competitive inhibition mechanism. This study demonstrates that the combination of the RINs with FEL on MD trajectories could be an effective method which can be extended to investigate allosteric communications for other macromolecular interaction systems.
Keywords:
Residue Interaction Networks, α-glucosidase Uncompetitive Inhibition, Allostery, Molecular Dynamics Simulation, Hotspot Residues.
Status : Paper Accepted (Poster Presentation)