Theoretical studies on the interactions of XIAP-BIR3 domain with bicyclic and tricyclic core monovalent Smac mimetics.
X-linked IAP can bind caspase-9 and inhibit its activity. Mitochondrial protein Smac/DIABLO can also interact with XIAP and relieve the inhibition on caspase-9 to induce apoptosis. A series of artificial Smac mimetics have been used to mimic the Smac N-terminal tetrapeptide AVPI to bind to XIAP-BIR3, but these structural diverse mimetics exhibited distinct binding affinities. To get an insight into the binding nature and optimize the structures, molecular docking and dynamics simulations were used to study the binding of XIAP-BIR3 with three groups of Smac mimetics. The docking results reveal that these Smac mimetics anchored on the surface groove of XIAP-BIR3 and superimposed well with AVPI. The modifications on the seven-membered ring of bicyclic core segment do not strengthen the binding affinity, while a benzyl introduced to the five-membered ring is favorable to the binding. Molecular dynamics simulations on three typical systems show that these complexes are very stable. Hydrogen bonds between the bicyclic core segment and Thr308 play critical roles in maintaining the stability of complex. The binding free energies calculated by MM_PBSA method are consistent with the experimental results.
Ling
Baoping
B
Key Lab of Colloid and Interface Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong 250100, China.
Dong
Lihua
L
Zhang
Rui
R
Wang
Zhiguo
Z
Liu
Yongjun
Y
Liu
Chengbu
C
D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D032701:Biomimetics; D018360:Crystallography, X-Ray; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008962:Models, Theoretical; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry* / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human