Molecular dynamic simulation of Trastuzumab F(ab')2 structure in corporation with HER2 as a theranostic agent of breast cancer

[摘要] Trastuzumab as intact IgG are well researched for theranostic agent in HER2 overexpressed breast cancer. However, due to the relatively large of molecules it is slowly moved and weak penetration of the target cells. Fragmentation of trastzumab has been developed by pepsin cleavages to get the F(ab')2fragments. To observe the stability and accessibility of F(ab')2structure in corporation with HER2 (human epidermal growth factor receptor-2), the structure of antibody modeling had been developed with 1IGT as a template. Molecular dynamics (MD) of the F(ab')2structure simulation has been done in the aqueous phase with AMBER trajectories for 20 ns. Computational visualization by VMD (Visual Molecular Dynamics) were applied to identify binding site interaction details between trastuzumab F(ab')2and HER2 receptor. The results of MD simulations indicated that the fragmentation of trastuzumab F(ab')2did not change the structure and conformation of F(ab')2as a whole, especially in the CDR (Complementarity Determining Region) area. SASA (solvent accessibility surface area) analysis on lysine residues showed that formation of conjugate DOTA-F(ab')2predicted occur on outside of the CDR regions so its not interfered with binding affinity for the HER2 receptor. The molecular dynamic simulation of DOTA-F(ab')2with HER2 receptor in aqueous system generated ΔGbindingmore highly (15.5066 kkal/mol) than positive control HER2-Fab (-45.1446 kkal/mol).

[发布机构] Department of Chemistry, Faculty of Mathematics and Science, University of Indonesia, Depok, Indonesia^1;Department of Chemistry, Faculty of Mathematics and Science, Padjadjaran University, Bandung, Indonesia^2;Study Program of Chemistry, Faculty of Science and Technology, Syarif Hidayatullah State Islamic University, Jakarta, Indonesia^3

[效力级别] 化学 [学科分类] 生物科学（综合）

[关键词] Binding affinities;Complementarity-determining regions;Computational visualization;Human epidermal growth factor;Lysine residues;Site interaction;Solvent accessibility;Theranostic agents