4.7 Article

Molecular basis of SMAC-XIAP binding and the effect of electrostatic polarization

Journal

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 39, Issue 2, Pages 743-752

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2020.1713892

Keywords

Computational alanine scanning; interaction entropy; hot spots; XIAP; BIR3 domain; BIR2 domain; SMAC; selectivity; GBSA; polarization; PPC

Funding

  1. National Key R&D Program of China [2016YFA0501700]
  2. National Natural Science Foundation of China [21433004, 91753103]
  3. NYU Global Seed Grant

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This study investigates the protein-peptide interaction between the BIR3 and BIR2 domains of XIAP and the SMAC peptide using molecular dynamics simulations and alanine scanning calculations. Energetic contribution of each binding residue and identification of hotspots reveal the importance of electrostatic polarization in stabilizing the protein-protein complex structure. By using polarized protein-specific charges, better agreement with experimental results is achieved for calculated binding free energies.
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.

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