Potency of a biotherapeutic is influenced by its binding affinity to the designated receptor. This study examines how substitution of methionine residues with Leucine/Alanine in granulocyte colony stimulating factor (G-CSF) brings about changes in its affinity to G-CSF receptor. To this effect, two mutants M1 (M122A, M127A and M138A) and M2 (M122L, M127L and M138L) were designed computationally and their stability and functional attributes were compared with the native GCSF. The simulation results show that although all atom root mean square deviations during 100 ns window were within 2–3 Å for the mutants as well as the native G-CSF, yet some local conformational changes were evident. Amino acid residues in the stretch 125–145 exhibited shift in their secondary structure composition from predominantly turn form to coiled and gamma turn forms. In addition, increase in the helical content in the amino acid stretch 60–70 was also observed when compared to native G-CSF. Docking and MMPBSA studies of the GCSF variants with G-CSFR show evidence of increased number of interactions with G-CSFR owing to the observed conformational perturbations in the variants. Experimental data on the stability and the affinity of these variants are in agreement with the in-silico predictions. Thus, we show that careful substitution of key residues in G-CSF potentially presents avenues for improving the stability as well therapeutic prospects of the molecule via enhancement in their affinities to the pertinent receptors.
Read full text: Avinash Mishra, Rucha S. Patil, Sumit Singh, Priyanka, Anurag S. Rathore, Mechanistic explanation of structural and functional changes induced by methionine mutation in G-CSF protein, Current Research in Biotechnology, Volume 2, 2020, Pages 37-44, https://doi.org/10.1016/j.crbiot.2020.01.002
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