Molecular Docking and Dynamics Simulation Study on the Influence of Zn²⁺ on the Binding Modes of Aggrecanase with its Inhibitors

Title:Molecular Docking and Dynamics Simulation Study on the Influence of Zn²⁺ on the Binding Modes of Aggrecanase with its Inhibitors

Volume: 17 Issue: 10

Author(s): Panneer S.R. Suganya, Sukesh kalva and Lilly M. Saleena

Affiliation:

Keywords: Aggrecanase, docking, MM-GBSA, molecular dynamics, zinc.

Abstract: Zinc plays a vital role in structural organization, regulation of function and stabilization of the folded protein, which ultimately activates or inactivates the binding sites of the protein. Its transition makes a major change in the protein and its binding affinity. The ligand binding aggrecanases can be influenced by Zn2+ ions; therefore the study focuses on checking the binding mode in the presence and absence of zinc using Docking and Molecular dynamics simulation. The crystal structure with zinc was considered as wild type (ADAMTS-4-1Zn²⁺, ADAMTS-5-1Zn²⁺) and the crystal structure without zinc was considered as the mutant type (ADAMTS-4-0Zn²⁺, ADAMTS-5-0Zn²⁺). Mutations were made manually by deleting the zinc atom. ADAMTS-4-1Zn²⁺ had the best Glide score of -12.66 kcal·mol⁻¹, whereas ADAMTS-4-0Zn²⁺ had -11.69 kcal·mol−1. ADAMTS-4-1Zn²⁺ had the best glide energy of -72.29 kcal·mol⁻¹, whereas ADAMTS-4-0Zn²⁺ had -68.44 kcal·mol⁻¹. ADAMTS-4-1Zn²⁺ had the best glide e-model of -116.34, whereas ADAMTS-4-0Zn²⁺ had -104.264. The RMSD value for ADAMTS-4-1Zn²⁺ and ADAMTS-4-0Zn2+ was 1.9. These results suggested that the absence of zinc decreases the binding affinity of ADAMTS-4 with its inhibitor. ADAMTS-5-1Zn²⁺ had the best Glide score of -8.32 kcal·mol⁻¹, whereas ADAMTS-5-0Zn²⁺ had -6.62 kcal·mol−1. ADAMTS-5-1Zn²⁺ had the best glide energy of -70.28 kcal·mol⁻¹, whereas ADAMTS-5-0Zn²⁺ had -66.02 kcal·mol⁻¹. ADAMTS-5-1Zn²⁺ had the best glide e-model of -108.484, whereas ADAMTS-5-0Zn²⁺ had -93.81. The RMSD value for ADAMTS-5-1Zn²⁺ and ADAMTS-5-0Zn2+ was 0.48Å. These results confirmed that the absence of zinc decreased the binding affinity of ADAMTS-5 with its inhibitor whereas the presence extended the docking energy range and strengthened the binding affinity. Per-residue interaction study, MM-GBSA and Molecular Dynamics showed that all the four complexes underwent extensive structural changes whereas the complex with zinc was stable throughout the simulation period.

Cite this article as:

Suganya S.R. Panneer, kalva Sukesh and Saleena M. Lilly, Molecular Docking and Dynamics Simulation Study on the Influence of Zn²⁺ on the Binding Modes of Aggrecanase with its Inhibitors, Combinatorial Chemistry & High Throughput Screening 2014; 17 (10) . https://dx.doi.org/10.2174/1386207317666141113155141