Biophysics
Mostafa Jamalan; Majid Zeinali; Ebrahim Asadabadi
Articles in Press, Accepted Manuscript, Available Online from 01 December 2013
Abstract
Overexpression and malfunction of epidermal growth factor receptors (EGFRs) is associated with occurrence of malignancy in various tissues. Among all members of EGFRs, HER2 as an orphan receptor dimerized and activated without presence of any kind of ligands has significant role in incidence of breast ...
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Overexpression and malfunction of epidermal growth factor receptors (EGFRs) is associated with occurrence of malignancy in various tissues. Among all members of EGFRs, HER2 as an orphan receptor dimerized and activated without presence of any kind of ligands has significant role in incidence of breast cancer. Herceptin as approved therapeutic monoclonal antibody targets extracellular domain of HER2 and inhibits its dimerization and prevents induction of intracellular signaling cascades. Efficiency of point mutation which offered based on rational design approach for affinity maturation of Herceptin was investigated by 10 ns of molecular dynamic simulation. According to our results, Herceptin with mutated light chain make a more stable complex with HER2 compared to its native type. Asp92 in mutated VL of Herceptin constructs a stable salt bridge with Lys569 on HER2, which decreases the electrostatic energy between VL of Herceptin and HER2, thereby affecting RMSD values of IV-HER2 during 10 ns of MD simulation. Herceptin (VL; Tyr92Asp)-HER2 complex has lower level of total energy during allover of MD simulation compared to Herceptin-HER2 complex. Although Herceptin has high Kd of 5 nM, it has great potential to be enhanced. Our molecular modeling investigation demonstrated that affinity maturation of Herceptin through rational design could be performed via mutation of Tyr92 to Asp in VL chain of antibody. Improvement of Herceptin affinity for HER2 could increase its efficiency and result to reduction of its dose or frequency of administrations.
