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

Abstract

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 inactive state of extracellular domain has not been clarified. The integrated model of Integrin αIIbβ3 was developed by combining the extracellular domain adopted from crystal structure and the transmembrane and intracellular domain obtained by NMR. The trans-membrane domain was settled into the phosphatidylcholine (POPC) lipid bilayer model. The position coordinates and velocity vectors of all atoms and water molecules around them were calculated by molecular dynamic simulation with the use of CHARMM (Chemistry at HARvard Macromolecular Mechanics) force field in every 2 x 10-15 sec. The root-mean-square deviations (RMSDs) of atoms constructing the integrated αIIbβ3 model apparently stabilized at approximately after 200 ns of calculation. However, minor fluctuation persisted during the entire calculation period of 650 ns. The RMSD of both αIIbβ3 showed similar trends before 200 ns. The RMSD of β3 3 apparently stabilized approximately at 400 ns with persisting minor fluctuation afterward while the structural fluctuation in αIIb persisted throughout the 650 ns calculation period. In conclusion, the integrated model of the intra-cellular, trans-membrane, and extra-cellular domain of integrin αIIb suggested persisting fluctuation even after convergence of molecular dynamic calculation.