Modeling the interactions between MC2R and ACTH models from human

Abstract

Melanocortin system is composed of four peptide hormones namely α-, β-, -γ, and adrenocorticotropic hormone (ACTH), derived from post-translational cleavage of a polypeptide precursor ‘proopiomelanocortin (POMC).’ Among these hormones, ACTH, a 38 amino acid residue peptide fragment is an important hormone as it is involved in steroid secretion. In addition to this, to cite a few, this hormone is also known to induce variety of other effects, such as alterations in motor/sexual behavior, improvement in memory, and anti-inflammatory effects. To date, five melanocortin receptors (MC1R–MC5R) have been characterized with tissue-specific expression patterns and different binding affinities for each of the melanocortin hormones to regulate various biological functions. In the present work, three-dimensional (3D) models of MC2R and ACTH from human have been predicted, followed by docking and molecular dynamics simulation. While the 3D model of MC2R receptor has been predicted through threading approach, structure of ACTH was built based on ab initio technique. The MC2R model was later successfully docked onto the ACTH structure. Molecular dynamics (MD) simulation for 20 ns was used to compute the binding free energy of MC2R with ACTH model under implicit solvent conditions.

Keywords:

• molecular dynamics
• melanocortin
• adrenocorticotropic hormone
• melanocortin 2 receptor
• binding energy

Acknowledgments

We are grateful to Dr Chenraj Roychand, Chairman, Jain Group of Institution, Dr Sudha Deshmukh, Dean (Sciences), CPGS, Jain U’sty, and Dr P.C. Deshmukh, Professor of Physics, Indian Institute of Technology, Chennai for creating the computational facilities. We also acknowledge Dr Sunil S. More, Dr Rathore, and Dr Abhay for giving useful points during the progress of this work. We also thank Mr Anand and his team members of Lintechnokrat, Bangalore for the efficient maintenance of our computer cluster system.

Notes

Abbreviations: ACTH: adrenocorticotropic hormone, POMC: proopiomelanocortin, MCR(s): melanocortin receptor (s), IGD: isolated glucocorticoid deficiency, CNS: central nervous system, MSH: melanocyte-stimulating hormone, UniProt: universal protein resource, PDB: protein data base, NMR: nuclear magnetic resonance, MD: molecular dynamics, AMBER: Assisted Model Building with Energy Refinement, VMD: Visual Molecular Dynamics, SANDER: simulated annealing with NMR-derived energy restraints, EL: extracellular loop, CL: cytoplasmic loop, RMSD: root mean square deviation, RMSF: root mean square fluctuation, cAMP: cyclic adenosine monophosphate.