Acetylation of lysin and N termini residues of human insulin: study on structural alterations

Acetylation of lysin and N termini residues of human insulin: study on structural alterations
reyhane kamelnia,¹ Bahram Goliaei ,^2,* Azadeh Ebrahim-Habibi ,³ Faramarz Mehrnejad,⁴
1. Institute of Biochemistry and Biophysics, University of Tehran
2. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
3. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
4. Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
Introduction: Acetylation is one of the major post-translation protein modification in the cells, with manifold effects at protein as well as the metabolome level. While acetylation may affect the structure of proteins and their subsequent aggregation, the consequences of aggregates formation are very important for pharmaceutical biologics such as insulinb [1,2].
Methods: In the present work, molecular dynamics simulation experiments, have been performed on native and acetylated forms of human insulin. Acetyl groups were added to GlyA1, PheB1 and LysB29 of the A and B chain, of insulin respectively). Three temperature of 37°C, 50°C and 100°C were used and both neutral and acidic pH environments effects were applied to. Molecular dynamic, MD, study was done in YASARA (17.3.30) for 3x-100ns MD simulations in NPT ensemble and using Amber 14 force field.
Results: The results showed that acetylation causes structural changes of insulin molecules which were accompanied with increase in protein surface hydrophobicity, and change in the secondary structure content (e.g. alpha-helix to beta –sheet transition which could be indicative of aggregation propensity) but this structural changes vary in different types of acetylated insulin. According to the data of RMSD, most changes related to acetylated forms of insulin in PheB1 and LysB29 of B chain also analysis of the secondary structure shows that the acetylated forms of insulin in PheB1 and LysB29 of B chain have the lowest content of beta-sheet in their structure. Acetylated insulin is less constrained geometrically and, as a result, more openly packed than native insulin[3,4].
Conclusion: The optimization of these modified insulin forms can lead to a better stabilized form of insulin and be potentially useful for the development of new therapeutic purposes with applied vision in the developing world.
Keywords: Insulin, lysin acetylation, Molecular dynamic, Simulation, Protein aggregation.