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Structural and Dynamic Insight into Hirudin Epitopes-HLADRB1 0101 Complexes and their Modified Peptide Ligands: A Molecular Dynamic Simulation Study Asgari, Saeme; Mirzahoseini, Hasan; Karimipour, Morteza & Ebrahim-Habibi, Azadeh Abstract Purpose: To develop a hirudin therapeutic protein that eliminates unwanted immune response. Methods: Molecular dynamic simulation was performed on immunodominant hirudin epitopes 1-15 and 13-27 and its analog, modified peptide ligands (MPLs), namely, [Lys4] Hir1-15 and [Gly9] Hir1-15, [Gly21] Hir13-27 and [Lys21] Hir13-27. The selected epitopes were modeled and 20 ns of molecular dynamics simulation was performed on peptide-HLA1 0101 and MPLs-HLA1 0101 complexes to gain a better understanding of molecular recognition mechanisms of MHC peptide binding. Characterization of the process was done by evaluation of root mean square deviation (RMSD) and total energy of binding. Result: All complexes of MPLs-HLA-DRB1 0101 showed thermodynamically unstable structure in comparison with native epitopes-HLA-DRB1 0101. The findings indicate that these analogs have different orientation in HLA grooves and are not available for suitable interaction with HLA-DRB1 0101. Conclusion: Altogether, the results show the potentials of predictive methods and molecular modeling in molecular mimicry of peptide-MHC interaction and provide insights into the binding characteristics of antigen presentation mechanism. Keywords Modified peptide ligand; Epitopes; MHC peptide binding; Hirudin; Modified peptide ligands; Molecular dynamic simulation; Binding free energy

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