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.