Deciphering the Binding Mechanism of PSMA-1007 to PSMA: Insights from Molecular Dynamics and Free Energy Landscapes

Abstract This study aimed to investigate the targeted binding mechanism of PSMA-1007 to prostate-specific membrane antigen (PSMA) at the atomic level, providing a theoretical basis for the rational design of PSMA-targeted drugs. We employed molecular dynamics (MD) simulations combined with the MM/PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) free energy calculation method. The results revealed a strong binding affinity with a total binding free energy of -75 kcal/mol, which was primarily driven by favorable electrostatic interactions. The stability of the complex was further supported by the persistent formation of a substantial number of hydrogen bonds (5 to 14) between PSMA-1007 and PSMA throughout the simulation. Free energy decomposition analysis identified key hotspot residues, including LYS699, ARG463, and TYR700, which made significant contributions to the binding. Quantitative assessment of the two major binding pockets showed that the S1 and S1' pockets contributed approximately 20% and 40% of the total favorable binding energy, respectively, highlighting the critical role and specificity of these subsites. In conclusion, our findings elucidate the dynamic binding process and energetic landscape of PSMA-1007, offering valuable insights for structure-based drug design targeting PSMA.