Calculation of hot spots for protein–protein interaction in p53/PMI-MDM2/MDMX complexes
Dading Huang
School of Physics and Material Science, Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
Search for more papers by this authorYifei Qi
School of Physics and Material Science, Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China
Search for more papers by this authorJianing Song
NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China
Search for more papers by this authorCorresponding Author
John Z. H. Zhang
School of Physics and Material Science, Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China
Department of Chemistry, New York University, New York, New York, 10003
Collaborative Innovation Center of Extreme Optics, Shanxi University, Taiyuan, Shanxi, 030006, China
John Z. H. Zhang, Department of Chemistry, New York University, New York, New York 10003
E-mail: [email protected]
Search for more papers by this authorDading Huang
School of Physics and Material Science, Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
Search for more papers by this authorYifei Qi
School of Physics and Material Science, Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China
Search for more papers by this authorJianing Song
NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China
Search for more papers by this authorCorresponding Author
John Z. H. Zhang
School of Physics and Material Science, Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China
Department of Chemistry, New York University, New York, New York, 10003
Collaborative Innovation Center of Extreme Optics, Shanxi University, Taiyuan, Shanxi, 030006, China
John Z. H. Zhang, Department of Chemistry, New York University, New York, New York 10003
E-mail: [email protected]
Search for more papers by this authorAbstract
The recently developed MM/GBSA_IE method is applied to computing hot and warm spots in p53/PMI-MDM2/MDMX protein–protein interaction systems. Comparison of the calculated hot (>2 kcal/mol) and warm spots (>1 kcal/mol) in P53 and PMI proteins interacting with MDM2 and MDMX shows a good quantitative agreement with the available experimental data. Further, our calculation predicted hot spots in MDM2 and MDMX proteins in their interactions with P53 and PMI and they help elucidate the interaction mechanism underlying this important PPI system. In agreement with the experimental result, the present calculation shows that PMI has more hot and warm spots and binds stronger to MDM2/MDMX. The analysis of these hot and warm spots helps elucidate the fundamental difference in binding between P53 and PMI to the MDM2/MDMX systems. Specifically, for p53/PMI-MDM2 systems, p53 and PMI use essentially the same residues (L54, I61, Y67, Q72, V93, H96, and I99) of MDM2 for binding. However, PMI enhanced interactions with residues L54, Y67, and Q72 of MDM2. For the p53/PMI-MDMX system, p53 and PMI use similar residues (M53, I60, Y66, Q71, V92, and Y99) of MDMX for binding. However, PMI exploited three extra residues (M61, K93, and L98) of MDMX for enhanced binding. In addition, PMI enhanced interaction with four residues (M53, Y66, Q71, and Y99) of MDMX. These results gave quantitative explanation on why the binding affinities of PMI-MDM2/MDMX interactions are stronger than that of p53-MDM2/MDMX although their binding modes are similar. © 2018 Wiley Periodicals, Inc.
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