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Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) is a 16.29 kDa cytokine that regulates the leukocyte production, migration and functions. The GM-CSF receptor ligand interaction stability plays vital role for prolonged differentiation of haematopoietic stem cell into granulocytes and monocytes. In the present investigation attempts were made to increase the number of stabilization centres in GM-CSF ligand using molecular simulation. This improves half-life stability of GM-CSF receptor ligand interaction complex. The numbers of stabilization centres were increased by amino-acid substitution which led to change in contact energy, hydrophobicity index and unfolding Gibbs free energy without altering receptor ligand interaction. Multiple sequence alignment of GM-CSF sequence using ClustalW with Ovies aries, Homo sapiens, Mus musculus and Gallus gallus species revealed the conserved domain regions and aminoacid dissimilarities in conserved and other regions. Based on the above, 21N, 25L, 42V, 55L, 56Q, 93E and 102T were mutated with its aminoacid substitution property. Different combinations of mutation were incorporated in the amino acid sequence and mutant proteins were modelled using structure of GM-CSF ligand (PDB ID: 1CSG) as a template by MODELLER. After mutation, the GLU21, LEU25, LEU55 and THR102 positions were identified as stability centre using SCide. Mutations at residues LEU55 and THR102 had 16.71% lesser energy value than the wild type GMCSF energy value which is 6831.73. The result suggested that, the stability of human GM-CSF has been increased (as the energy decreases) due to mutagenesis by computational tools.