Development of the Integrated Computer Simulation Model of the Intracellular, Transmembrane, and Extracellular Domain of Platelet Integrin α_IIbβ₃ (Platelet Membrane Glycoprotein: GPIIb–IIIa)

Abstract

Background The structure and functions of the extracellular domain of platelet integrin α_IIbβ₃ (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_IIbβ₃ with the inactive state of the extracellular domain has not been clarified.

Methods The integrated model of integrin α_IIbβ₃ 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_IIbβ₃ 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 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 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_IIbβ₃ suggested persisting fluctuation even after convergence of MD calculation.

Keywords

platelet - integrin α_IIbβ₃ - molecular dynamic simulation - GPIIb/IIIa

^* The contribution of Shinichi Goto on this paper is equal to Masamitsu Nakayama.

Publication History

Received: 11 May 2023

Accepted: 04 January 2024

Accepted Manuscript online:
17 January 2024

Article published online:
29 February 2024

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