Exploration of Curcumin and HER2 ICD Interaction Processes Using Unguided Molecular Dynamics Simulation, Coarse-Grained Modelling, and Free Energy Analysis
Retno Dewi Purnawati* and Acep Purqon

Physics Study Program, Institut Teknologi Bandung

Abstract

HER2 (ERBB2) overexpression occurs in approximately 20-30% of breast cancer cases and correlates with disease aggressiveness and poor prognosis. Although antibody-based therapies and tyrosine kinase inhibitors have been developed, the presence of side effects and therapeutic resistance encourages the search for safer alternatives, including natural compounds like curcumin. However, the structural and energetic understanding of the interaction between curcumin and HER2, particularly at the intracellular domain, remains limited. This study investigates the interaction between curcumin and the HER2 intracellular domain (ICD) using molecular dynamics (MD) simulations with coarse-grained (CG) modelling and the Martini 2.2 force field. The HER2 ICD structure (PDB: 3RCD) was reconstructed and solvated in a box containing water and 0.15 M NaCl. Four models were constructed by integrating curcumin at four different initial positions. Each model was simulated in triplicate for 1 microsecond each, resulting in a total simulation time of 12 microseconds. The simulation results indicate that curcumin does not bind to a single specific site but instead dynamically explores the protein surface. Free energy calculations using the free energy perturbation (FEP) method with a flat-bottom potential were performed to evaluate the thermodynamic profile of the interaction. This study demonstrates that the combination of CG-MD and FEP is an efficient approach for exploring protein-ligand interactions and provides new insights into the potential of curcumin as a modulator of HER2 function.

Keywords: HER2 (ERBB2)- Curcumin- Coarse-grained molecular dynamics- Free energy perturbation

Topic: Medical Physics and Biophysics