MD trajectories demonstrating the role of stochastic resonance in triggering the EPCR-Vorapaxar unbinding.

MD trajectory of simulation of the extracellular domain of EPCR with bound PCGla domain and two Vorapaxar (VPX) ligands.The EPCR-ligands system simulated at 10 degrees for 10 ns at 1 THz sampling rate allowed to observe partial unbinding of VPX. Two regions of VPX (carbamic acid tail and central naphtho-furan containing regions) were detached from EPCR b-sheet, while fluorophenyl-pyridin region of VPX bound to b-sheet remained in contact with EPCR. The trajectory of the same system simulated at 37 degrees demonstrated that all three fragments of VPX remained in contact with EPCR, although local reorientation of VPX was observed. VPX bound in the hydrophobic cleft of EPCR formed by two a-helices remained in contact with EPCR at both temperatures at all times with occasional reorientation of bound molecule. The system contained 53650 atoms including EPCR, PCGla domain, two VPX molecules, and water molecules.NAMD software and CHARMM36m improved force field with TIP3 water model were used for simulations. The original trajectories were saved with stride 4, to generate the uploaded 1.6 GB trajectory files (epcr_gla_2vpx2500ts_10degr.dcd and epcr_gla_2vpx2500ts_37degr.dcd) each containing 2500 time steps. Protein structure files corresponding to the trajectory files are epcr_gla_2vpx2500ts_10degr.psf and epcr_gla_2vpx2500ts_37degr.psf, respectively.