α-Glucosidase Un-Competitive Inhibition investigation via Residual Interaction Network, and Free Energy Landscapes: ۰.۵ μs Molecular Dynamics Simulations

Residual Interaction Network (RIN) analyses combined with molecular dynamics (MD) simulations haveshown to be a powerful tool for the analysis of protein conformational dynamics, that plays a key role in theallosteric mechanism of enzymes. Here, with the coherence between RIN analysis and Free EnergyLandscapes (FEL), two ۲۵۰ ns trajectories are compared, which were created by MD simulations on free andxanthene 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 conformationallandscape of α-glucosidase and its complex to identify the representative of their sub-states. By integratingthe networks of each basin conformations, and creating the mean network for each one, four intermediatenetworks of α-glucosidase were created. We also utilize the Girvan-Newman algorithm to detect communitiesand its interactions as a structural organization in α-glucosidase. The role of residues with large variations inthe 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 ligandbinding,and their communities are identified. So, the structure of α-glucosidase is well organized withdifferent communities acting different roles in the ligand binding and allosteric un-competitive inhibitionmechanism. This study demonstrates that the combination of the RINs with FEL on MD trajectories couldbe an effective method which can be extended to investigate allosteric communications for othermacromolecular interaction systems.

Keywords:

Residue Interaction Networks , α-glucosidase Uncompetitive Inhibition , Allostery , Molecular Dynamics Simulation , Hotspot Residues