Abstract
Context
Cyclophilin A (CypA) is a peptidyl-prolyl cis/trans isomerase involved in various critical cellular processes, including protein folding, trafficking, and immunomodulation. Its role in the pathogenesis of several human diseases, including viral infections, cancer, and inflammatory conditions, makes it a significant target for therapeutic intervention. This study aims to elucidate the structural and dynamic changes in CypA upon binding with its potent inhibitor, SangfA, using molecular dynamic simulations (MDS). The potential impact of these findings on our understanding of disease mechanisms and the development of novel therapeutic strategies is highly anticipated.
Methods
MDS was conducted using GROMACS 5.1.4 to explore the interaction between CypA and SangfA. The crystallographic structure of CypA (PDB ID: 1BCK) was obtained from The Protein Data Bank and prepared using UCSF Chimera 1.10.2. The structures of known CypA inhibitors were sourced from PubChem. Docking studies were performed using Autodock Vina, and the grid box coordinates were set with Autodock Tools 1.5.6. The MDS involved solvating the CypA-SangfA complex in a simple point-charge water box under periodic boundary conditions. The system was neutralized, followed by steepest descent energy minimization and equilibration. A 100 ns MD simulation was conducted to evaluate the system's stability. The built-in tools in GROMACS were utilized to analyze Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), hydrogen bonding, and Solvent Accessible Surface Area (SASA). The Linear Interaction Energy (LIE) method was utilized to estimate binding free energy, and principal component analysis (PCA) was carried out to detect significant conformational alterations. All simulations were executed on a Core i7 system with an NVidia GeForce GPU.