caa a22 4500 605513538 CHVBK 20210128100700.0 cr unu---uuuuu 210128e20150201xx s 000 0 eng 10.1007/s00894-015-2580-x doi (NATIONALLICENCE)springer-10.1007/s00894-015-2580-x Atomistic insights into the lung cancer-associated L755P mutation in HER2 resistance to lapatinib: a molecular dynamics study [Elektronische Daten] [Bei Yang, Haiping Zhang, Hao Wang] HER2, a member of the human ErbB protein family belonging to receptor tyrosine kinases, plays important roles in regulating crucial cellular processes, including cell migration, proliferation, and differentiation. A missense mutation, L755P, in the HER2 kinase domain has been involved in lung cancer in humans and exhibits reduced response to lapatinib therapy. However, the detailed mechanism of how the HER2 L755P mutation causes drug resistance to lapatinib remains elusive. Here, molecular docking, molecular dynamics (MD) simulations, binding free energy calculations [molecular mechanics and generalized Born/surface area (MM-GBSA)] were performed to reveal the mechanism of drug resistance due to the HER2 L755P mutation. MD simulations revealed that the L755P mutation caused structural changes in the regions of helix αC, the glycine-rich loop, and the activation loop, thereby leading to the loss of interactions between the solubilizing group of lapatinib and HER2. Moreover, MM-GBSA calculations suggested that hydrophobic interactions between lapatinib and HER2 contribute most to the binding affinity, and that the L755P mutation could result in a less energetically favorable HER2/lapatinib complex. This may weaken the binding of lapatinib to the mutated HER2, thereby leading to the emergence of drug resistance. This study offers a structural explanation for the effect of the L755P mutation on the HER2/lapatinib complex. Graphical Abstract In the present study, molecular docking, molecular dynamics (MD) simulations, MM-GBSA binding free energy calculations, were performed to reveal the mechanism of drug-resistance due to the HER2 L755P mutation. Springer-Verlag Berlin Heidelberg, 2015 HER2 nationallicence MD simulation nationallicence Lung cancer nationallicence MM-GBSA nationallicence Drug-resistance nationallicence Yang Bei Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, 200433, Shanghai, China aut Zhang Haiping Department of Oncology, Shanghai Pulmonary Hospital, Tongji University, 200433, Shanghai, China aut Wang Hao Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, 200433, Shanghai, China aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/2(2015-02-01), 1-12 1610-2940 21:2<1 2015 21 894 https://doi.org/10.1007/s00894-015-2580-x text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2580-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Yang Bei Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, 200433, Shanghai, China aut NATIONALLICENCE 700 1- Zhang Haiping Department of Oncology, Shanghai Pulmonary Hospital, Tongji University, 200433, Shanghai, China aut NATIONALLICENCE 700 1- Wang Hao Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, 200433, Shanghai, China aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/2(2015-02-01), 1-12 1610-2940 21:2<1 2015 21 894