## 3 Results
### Molecular Dynamics Simulations
The results revealed that Rg values across all complexes exhibited slight variations, ranging from 1.707 to 1.739 nm. The average Rg values calculated for the HSP90_L1, HSP90_L2, and HSP90_MEY complexes were 1.724 nm, 1.739 nm, and 1.707 nm, respectively. The HSP90 configuration remained unchanged in the presence of the proposed inhibitors, maintaining a stable radius of gyration throughout the 300 ns simulation period, indicating the stability of all complexes. Figure 6 shows the radius of gyration. The solvent-accessible surface area (SASA) predicts the dynamic changes observed during the interaction time. Figure 7 shows SASA profiles for each system during 300 ns of simulation. The average solvent-accessible surface area for the reference system measured 111.869 nm\({}^{2}\), while for the complexes HSP90_L1 and HSP90_L2, the average SASA values were 112.311 nm\({}^{2}\) and 113.561 nm\({}^{2}\), respectively. The SASA reached a stable equilibrium throughout the simulation, suggesting that the configurations of HSP90 remained stable in the presence of the proposed inhibitors (L1 and L2). This consistency helps elucidate how the proposed molecules interact with the active site of HSP90 and consistently bind during molecular binding. Figure 5: Backbone atomic variability in HSP90 and its complexes: RMSF analysis. Figure 6: Radius of gyration profiles for each complex during 300 ns of simulation. These findings align with previous research, specifically the docking study, which demonstrates that the proposed compounds form highly stable complexes with the HSP90 protein and effectively inhibit its crucial function. Moreover, snapshots of the three systems were taken at intervals of 100 to 300 ns. Analysis of the binding poses of each complex confirms their stability throughout the simulation period, as shown in Figure 8.  
Figure 8: Binding poses of the three systems during 300 ns of simulation. Figure 7: SASA profiles for each system over 300 ns of simulation. Free Energy Landscape  
The FEL (free energy landscape) technique is instrumental in identifying the representative conformational state of a system. This state is ascertained by pinpointing the minimum on the FEL, which represents the most stable structural minimum or the equilibrated conformational state. To examine the structural shift of the HSP90 protein following the biomolecular interactions in each system, we generated an FEL to illustrate changes in the protein's configuration. We utilized two specific reaction parameters for the FEL analysis: the RMSD of the HSP90 protein, which reflects the protein's structural stability over 300 ns of simulation, and the Rg, which provides insight into the protein's folding behavior. Figure 9 depicts the FEL right after interactions with HSP90 and the L1, L2, and MEY molecules. First, we identified a prominent well at RMSD values of 0.140 to 0.200 nm and Rg values of 1.65 to 1.73 nm when HSP90 interacted with the proposed molecule L1. In addition, upon interaction with the second proposed molecule L2, a distinct well was observed, concentrated at Rg values of 1.67 to 1.74 nm and RMSD values of 0.11 to 0.30 nm. On the other hand, across interactions with the reference medication (MEY), we definitely identified a centered zone at RMSD (0.12, 0.25 nm) and Rg (1.64, 1.71 nm). The simulations suggest that the low-energy regions on the free energy maps indicate a reasonably stable biomolecular structure and dynamics. Compounds L1 and L2 form highly stable complexes with the protein receptor, unlike the medication MEY, as further corroborated by the conspicuous wells seen in the free energy landscape maps when these molecules are attached to the HSP90 receptor. Finally, the extraction of HSP90 structures from the three regions indicated minimal conformational changes in the HSP90 configurations following interaction with the proposed inhibitors. Figure 9: Free energy landscape as a function of RMSD and Rg; (**A**) HSP90_L1, (**B**) HSP90_L2, (**C**) HSP90_MEY and the extracted HSP90 structures from minimum energy.