Development of the Integrated Computer Simulation Model of the Intracellular, Transmembrane, and Extracellular Domain of Platelet Integrin αIIbβ3 (Platelet Membrane Glycoprotein: GPIIb–IIIa)

Abstract

Background The structure and functions of the extracellular domain of platelet integrin αIIbβ3 (platelet membrane glycoprotein: GPIIb–IIIa) change substantially upon platelet activation. However, the stability of the integrated model of extracellular/transmembrane/intracellular domains of integrin αIIbβ3 with the inactive state of the extracellular domain has not been clarified. Methods The integrated model of integrin αIIbβ3 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 αIIbβ3 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 αIIb and β3 showed similar trends before 200 ns. The RMSD of β3 apparently stabilized approximately at 15 Å at 400 ns with persisting minor fluctuation afterward, while the structural fluctuation in αIIb persisted throughout the 650 ns calculation period. Conclusion In conclusion, the integrated model of the intracellular, transmembrane, and extracellular domain of integrin αIIbβ3 suggested persisting fluctuation even after convergence of MD calculation.