Molecular dynamics simulation of the dissociation mechanism of P-selectin from PSGL-1

Abstract

Interactions between P-selectin, expressed on activated endothelium, and its counterpart P-selectin glycoprotein ligand-1 (PSGL-1), expressed on leukocytes, play a pivotal role in adhesive events that recruit circulating leukocytes toward inflamed or injured tissues. Atomistic understanding of the association and dissociation of these bonds under blood flow is necessary to define the underlying mechanism. In this study, steered molecular dynamics (SMD) simulations were applied to investigate the conformational changes of P-LE/SGP-3 construct (an effective binding unit of the P-selectin/PSGL-1 complex) under stretching with constant velocity. In the present simulations, a self-built force field parameterization was developed for sulfated tyrosine by using force field toolkit of Visual Molecular Dynamics (VMD) program. A dissociation mechanism was represented by analyzing the nonbonded energies between interface residues. The results indicate that the salt bridges between P-LE and SGP-3 and the hydrogen bonds between ion Ca[Formula: see text] and residue fucose of glycan group of PSGL-1 and also between sulfated tyrosine residues are the most effective bonds in binding. Finally, potential of mean force (PMF) was calculated by averaging the outcomes of eight independent runs and the results were discussed.