biostudies-literatureYang WKey Research and Development Project of the Shandong ProvinceShandong Jiaotong UniversityNatural Science Foundation of Shandong Province3377https://www.ebi.ac.uk/biostudies/studies/S-EPMC11279683biostudies-literatureUnknown29(14)Inhibiting MDM2-p53 interaction is considered an efficient mode of cancer treatment. In our current study, Gaussian-accelerated molecular dynamics (GaMD), deep learning (DL), and binding free energy calculations were combined together to probe the binding mechanism of non-peptide inhibitors K23 and 0Y7 and peptide ones PDI6W and PDI to MDM2. The GaMD trajectory-based DL approach successfully identified significant functional domains, predominantly located at the helixes α2 and α2', as well as the β-strands and loops between α2 and α2'. The post-processing analysis of the GaMD simulations indicated that inhibitor binding highly influences the structural flexibility and collective motions of MDM2. Calculations of molecular mechanics-generalized Born surface area (MM-GBSA) and solvated interaMolecules (Basel, Switzerland)Insights into the Interaction Mechanisms of Peptide and Non-Peptide Inhibitors with MDM2 Using Gaussian-Accelerated Molecular Dynamics Simulations and Deep Learning.PMC112796832019GGX102050ZR2021MA069TJXZ202204Yang WZhao LChen JWang JfalseInsights into the Interaction Mechanisms of Peptide and Non-Peptide Inhibitors with MDM2 Using Gaussian-Accelerated Molecular Dynamics Simulations and Deep Learning.Inhibiting MDM2-p53 interaction is considered an efficient mode of cancer treatment. In our current study, Gaussian-accelerated molecular dynamics (GaMD), deep learning (DL), and binding free energy calculations were combined together to probe the binding mechanism of non-peptide inhibitors K23 and 0Y7 and peptide ones PDI6W and PDI to MDM2. The GaMD trajectory-based DL approach successfully identified significant functional domains, predominantly located at the helixes α2 and α2', as well as the β-strands and loops between α2 and α2'. The post-processing analysis of the GaMD simulations indicated that inhibitor binding highly influences the structural flexibility and collective motions of MDM2. Calculations of molecular mechanics-generalized Born surface area (MM-GBSA) and solvated intera2024-01-01T00:00:00Z2024 Jul2026-04-21T03:30:23.375Z2025-04-19T13:13:08.68ZS-EPMC112796833906495510.3390/molecules29143377