Development of the Integrated Computer Simulation Model of the Intracellular, Transmembrane, and Extracellular Domain...

Background  The structure and functions of the extracellular domain of platelet integrin α _IIb β ₃ (platelet membrane glycoprotein: GPIIb-IIIa) change substantially upon platelet activation. However, the stability of the integrated model of extracellular/transmembrane/intracellular domains of integrin α _IIb β ₃ with the inactive state of the extracellular domain has not been clarified. Methods  The integrated model of integrin α _IIb β ₃ was developed by combining the extracellular domain adopted from the crystal structure and the transmembrane and intracellular domain obtained by Nuclear Magnetic Resonace (NMR). The transmembrane domain was settled into the phosphatidylcholine (2-oleoyl-1-palmitoyl-sn-glycerol-3-phosphocholine (POPC)) lipid bilayer model. The position coordinates and velocity vectors of all atoms and water molecules around them were calculated by molecular dynamic (MD) simulation with the use of Chemistry at Harvard Macromolecular Mechanics force field in every 2 × 10 ^-15 seconds. Results  The root-mean-square deviations (RMSDs) of atoms constructing the integrated α _IIb β ₃ model apparently stabilized at approximately 23 Å after 200 ns of calculation. However, minor fluctuation persisted during the entire calculation period of 650 ns. The RMSDs of both α _IIb and β ₃ showed similar trends before 200 ns. The RMSD of β ₃ apparently stabilized approximately at 15 Å at 400 ns with persisting minor fluctuation afterward, while the structural fluctuation in α _IIb persisted throughout the 650 ns calculation period. Conclusion  In conclusion, the integrated model of the intracellular, transmembrane, and extracellular domain of integrin α _IIb β ₃ suggested persisting fluctuation even after convergence of MD calculation.