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Published on: December 12, 2014
Molecular basis of SMAC-XIAP binding and the effect of electrostatic polarization
Shuaizhen Tian1, Changge Ji1,2, John Z H Zhang1,2,3,4
1State Key Laboratory of Precision Spectroscopy and Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai, China.
Abstract:
X-chromosome-linked inhibitor of apoptosis (XIAP) inhibits cell apoptosis. Overexpression of XIAP is widely found in human cancers. Second mitochondria-derived activator of caspase (SMAC) protein inhibits XIAP through binding with Baculovirus Inhibitor of apoptosis protein Repeat (BIR) 3 or BIR2 domain of XIAP. In this study, molecular dynamics (MD) simulations and the alanine scanning calculations by MM-GBSA_IE method were used to investigate the protein-peptide interaction between BIR3 and BIR2 domains of XIAP and SMAC peptide. Energetic contribution of each binding residue is calculated and hotspots on both XIAP and SMAC were identified using computational alanine scanning with interaction entropy method. We found that electrostatic polarization is important in stabilizing the protein-protein complex structure in MD simulation. By using polarized protein-specific charges, much better agreement with experimental result is obtained for calculated binding free energies compared to those using standard (nonpolarizable) AMBER force field. In particular, excellent correlation between calculated binding free energies in alanine scanning with mutational experimental data was obtained for BIR3/SMAC binding.Communicated by Ramaswamy H. Sarma.
Insights
This study reveals how the SMAC peptide binds to XIAP, a protein involved in cancer. Computational methods identified key interaction points, improving our understanding of cancer cell survival mechanisms.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- X-chromosome-linked inhibitor of apoptosis (XIAP) is a protein that inhibits programmed cell death (apoptosis).
- Overexpression of XIAP is frequently observed in various human cancers, contributing to tumor development and resistance to therapy.
- The Second Mitochondria-derived Activator of Caspase (SMAC) protein antagonizes XIAP function by binding to its Baculovirus Inhibitor of Apoptosis Protein Repeat (BIR) domains.
Purpose of the Study:
- To investigate the molecular interactions between the BIR3 and BIR2 domains of XIAP and the SMAC peptide using computational methods.
- To identify critical binding residues (hotspots) on both XIAP and SMAC involved in their interaction.
- To evaluate the role of electrostatic polarization in stabilizing the protein-peptide complex and compare computational binding free energies with experimental data.
Main Methods:
- Molecular Dynamics (MD) simulations were employed to model the dynamic behavior of the XIAP-SMAC complex.
- The MM-GBSA_IE (Molecular Mechanics with Generalized Born Surface Area and Interaction Entropy) method was used for alanine scanning calculations.
- Computational alanine scanning was performed to determine the energetic contribution of individual binding residues.
Main Results:
- Electrostatic polarization was identified as a significant factor in stabilizing the protein-peptide complex structure during MD simulations.
- Utilizing polarized protein-specific charges yielded calculated binding free energies with significantly better agreement to experimental results compared to standard nonpolarizable force fields.
- A strong correlation was observed between the calculated binding free energies from alanine scanning and experimental mutational data for the BIR3/SMAC binding interaction.
Conclusions:
- The study provides detailed insights into the molecular mechanisms governing the XIAP-SMAC interaction at the atomic level.
- The findings highlight the importance of electrostatic polarization in protein-protein interactions and suggest that polarized force fields improve binding free energy calculations.
- The accurate prediction of binding affinities through computational alanine scanning validates its utility for identifying key residues and guiding drug design targeting XIAP in cancer therapy.
