Multi-scale simulation of L-selectin-PSGL-1-dependent homotypic leukocyte binding and rupture.
L-selectin-PSGL-1-mediated polymorphonuclear (PMN) leukocyte homotypic interactions potentiate the extent of PMN recruitment to endothelial sites of inflammation. Cell-cell adhesion is a complex phenomenon involving the interplay of bond kinetics and hydrodynamics. As a first step, a 3-D computational model based on the Immersed Boundary Method is developed to simulate adhesion-detachment of two PMN cells in quiescent conditions. Our simulations predict that the total number of bonds formed is dictated by the number of available receptors (PSGL-1) when ligands (L-selectin) are in excess, while the excess amount of ligands influences the rate of bond formation. Increasing equilibrium bond length results in a higher number of receptor-ligand bonds due to an increased intercellular contact area. On-rate constants determine the rate of bond formation, while off-rates control the average number of bonds by modulating bond lifetimes. Application of an external pulling force leads to time-dependent on- and off-rates and causes bond rupture. Moreover, the time required for bond rupture in response to an external force is inversely proportional to the applied load and decreases with increasing off-rate.
Department of Mechanical Engineering, University of Maryland, Baltimore, 21250, USA.
V K
VK
Gupta
Ihab A
IA
Sraj
Konstantinos
K
Konstantopoulos
Charles D
CD
Eggleton
D003198:Computer Simulation; D007700:Kinetics; D019041:L-Selectin / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism
D008024:Ligands; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D011956:Receptors, Cell Surface; D019041:L-Selectin