Informatics Publishing Limited

Anuj Ranjan ¹, Joyce S. F. D. De Almeida ², Tanos C. C. Franca ², Abhishek Chauhan ¹, Saradindu Ghosh ³, Tanu Jindal ¹

Affiliations
1 Amity Institute of Environmental Toxicology, Safety and Management, Institute of Engineering, Praca General Tiburcio 80, 22290-270, Rio de Janeiro, BR
2 Laboratory of Molecular Modeling Applied to Chemical and Biological Defense (LMACBD), Military Institute of Engineering, Praca General Tiburcio 80, 22290-270, Rio de Janeiro, BR
3 Amity Institute of Biotechnology, Amity University, Noida, IN

Abstract

Molecular Docking, site directed mutagenesis and molecular dynamic (MD) simulation approaches were used to explore mode of binding and inhibition for human acetylcholinesterase (hAChE) and organophosphates (OPs). More than 200 OPs molecules were investigated using Glide docking module of Schrodinger suite as co-crystal structure between two are not available in protein data bank. In initial screening Trp86 was found to be involved in maximum π-cation interaction on anionic subsite of hAChE other than Ser203 (catalytic site). With extra precision glide docking phoxim ethyl phosphonate (PEP) tops among 200 OPs based on glide docking score while interacted with Trp86, Gly121 and Ser203 whereas MMGBSA score shows less binding affinity than heptenophos and dichlorovos. Trp86 preferred π interaction with ring bearing OPs and hydrophobic interactions with smaller OPs without ring bearing structures. Site directed mutagenesis at Trp86 (Trp86 to Ala86) shown the deterioration of the binding site in terms of size reduction, loss of electrostatic and geometric stabilization in binding cavity and significant reduction in binding of OPs in preferred orientation. Dock score of both wild and mutated hAChE shows a perfect qualitative agreement (R²=64.1%) towards the study. Molecular dynamic simulation (GROMACS 4.5.5) of hAChE-PEP complex for 4×10⁴ pico-second with SPC16 water system at 310K temperature explained the evident role of Trp86 in stabilizing the ligand at P-site of the enzyme. Asp74 and Tyr 124 were noticed in conveying H-bonds. Trp86 have shown consistent and stable distance between residues and ligand. Asp74 and Tyr124 appeared as important residues which contributed H bonds and Ser203 was expected to be closer for interaction to happen as it disappeared during simulation. Study suggests role of Trp86 on binding site is equally important to take consideration. As residue Trp86 plays significant role, it can be taken into consideration for the studies on development of more efficient antidotes to overcome the case of human poisoning.

Keywords

Docking, Molecular Dynamic Simulation, Human Acetylcholinesterase, Organophosphates.

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