Abstract
The study of the p53-MDMX/MDM2 binding sites is a research hotspot for tumor drug design. The inhibition of p53-targeted MDMX/MDM2 has become an effective approach in anti-tumor drug development. In this paper, a theoretically rigorous and computationally accurate method, namely, the interaction entropy (IE) method, combined with the polarized protein-specific charge (PPC) force field, is used to explore the difference in the binding mechanism between p53-MDMX and p53-MDM2. The interaction of a 12mer peptide inhibitor (pDIQ), which is similar to p53 in structure, with MDMX/MDM2 is also studied. The results demonstrate that p53/pDIQ with MDM2 generates a stronger interaction than with MDMX. Compared to p53, pDIQ has larger binding free energies with MDMX and MDM2. According to the calculated binding free energies, the differences in the binding free energy among the four complexes that are obtained from the combination of PPC and IE are more consistent with the experimental values than with the results from the combination of the non-polarizable AMBER force field and IE. In addition, according to the decomposition of the binding free energy, the van der Waals (vdW) interactions are the main driving force for the binding of the four complexes. They are also the main source of the weaker binding affinity of p53/pDIQ-MDMX relative to p53/pDIQ-MDM2. Compared with p53-MDMX/MDM2, according to the analysis of the residue decomposition, the predicated total residue contributions are higher in pDIQ-MDMX/MDM2 than in p53-MDMX/MDM2, which explains why pDIQ has higher binding affinity than p53 with MDMX/MDM2. The current study provides theoretical guidance for understanding the binding mechanisms and designing a potent dual inhibitor that is targeted to MDMX/MDM2.
Highlights
Protein-Protein interactions play an important role in the recognition of numerous biological processes and biomacromolecules (Pawson and Nash, 2000; Wang et al, 2001; Keskin et al, 2008)
The non-polarized AMBER force field and the protein-specific charge (PPC) force field, combined with the newly developed interaction entropy (IE) method, are used to explore the interaction mechanisms of p53 and 12mer peptide inhibitor pDIQ with MDMX/MDM2
The IE method makes full use of all samplings that are obtained from the Molecular dynamics (MD) simulation, thereby providing accurate and effective results without increasing the computational cost
Summary
Protein-Protein interactions play an important role in the recognition of numerous biological processes and biomacromolecules (Pawson and Nash, 2000; Wang et al, 2001; Keskin et al, 2008). Investigating protein-protein interactions at the atomic level via MD simulation can yield quantitative information and is helpful for understanding the microscopic mechanisms of biological processes. The design of drugs based on protein-protein interactions has been become a hot topic. The binding strength between two proteins is determined by the binding free energy. Accurate calculation of the binding free energy is vital for investigating the interaction mechanism and is helpful for drug design. Drug-like molecules tend to bind to hot areas (Burgoyne and Jackson, 2006; Cheung et al, 2012) in protein-protein interaction surfaces
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
