Atomistic Simulation Combined with Analytic Theory To Study the Response of the P-Selectin/PSGL-1 Complex to an External Force

Abstract

Steered molecular dynamics simulations are combined with analytic theory in order to gain insights into the properties of the P-selectin/PSGL-1 catch-slip bond at the atomistic level of detail. The simulations allow us to monitor the conformational changes in the P-selectin/PSGL-1 complex in response to an external force, while the theory provides a unified framework bridging the simulation data with experiment over 9 orders of magnitude. The theory predicts that the probability of bond dissociation by the catch mechanism is extremely low in the simulations; however, a few or even a single trajectory can be sufficient for characterization of the slip mechanism. Theoretical analysis of the simulation data shows that the bond responds to the force in a highly nonlinear way, with the bond stiffness changing considerably as a function of the force ramp rate. The Langevin description of the simulation provides spring constants of the proteins and the binding interaction and gives the friction coefficient associated with the receptor-ligand motion in water. The estimated relaxation time shows that the simple probabilistic description is accurate for the experimental regime and remains approximately valid for the high ramp rates used in simulations. The simulations establish that bond deformation occurs primarily within the P-selectin receptor region. The two interaction sites within the binding pocket dissociate sequentially, raising the possibility of observing these independent rupture events in experiment. The stronger interaction that determines the overall properties of the bond dissociates first, indicating that the experimental data indeed capture the main rupture event and not the secondary weaker site rupture. The main rupture event involves the interaction between the calcium ion of the receptor and the ligand residue FUC-623. It is followed by new interactions, supporting the sliding-rebinding behavior observed in the earlier simulation [ Lou, J. Zhu, C. Biophys. J. 2007 , 92 , 1471 - 1485 ]. The weaker binding site shows fewer interaction features, suggesting that the sliding-rebinding behavior may be determined by the unique properties of the calcium site. The agreement between simulation and experiment provided by the two-pathway and deformation models, each containing only four parameters, indicates that the essential physics of the catch-slip bond should be relatively simple and robust over a wide range of pulling regimes.

Deformation Model for Thioredoxin Catalysis of Disulfide Bond Dissociation by Force

“…The model successfully described the behavior of the P-selectins/ PSGL-1 17 and actin/myosin 10 bonds, see Pereverzev and co-workers, 18,22 respectively. Recent atomistic simulations 9,16,27 as well as experimental data 1 support the deformation interpretation of catch-binding by showing that the proteins forming the bonds undergo large-scale conformational changes involving the binding pocket. The deformation concept allowed us to rationalize not only the catch-behavior but also the large discrepancies between the bond dissociation rate constants obtained by extrapolating the finite force data to zero force and directly without force.…”

Advances in Experiments and Modeling in Micro- and Nano-Biomechanics: A Mini Review

“…55 SMD simulations on unbinding of receptor from its ligand, such as P-selectin glycoprotein ligand 1 (PSGL-1) from P-selectin and glycoprotein Iba (GPIba) from vWF-A1, have provided insights into the molecular mechanism underlying catch-bond. 32,40,58,103 Flow MDS was inspired from FC assay and first carried out by Lou and Zhu 59 and further improved by Chen et al…”

“…Two-pathway model and deformation model are developed to depict the transition from catch-bond to slip-bond in receptor-ligand interaction under forces. 32 Force-dependent association models have provided a way to estimate reverse rate of receptor unbinding from its ligand in AFM, OT, and BFP assays as well as DFS measurements. To date, the force dependence of reverse rate of receptor-ligand interaction has been intensively studied by different methods, including lifetime and rupture force measurements of single bonds or tether and rupture force measurements of single cell.…”

Bioinformatics and molecular modeling in glycobiology

“…However, experimental results are very important for validating the quality of theoretical calculations. In recent years, MD simulations have been used to study conformations of complex carbohydrates [206–209], glycolipids [200, 210, 211], glycopeptides [212], glycoproteins [213, 214], protein–carbohydrate complexes [215–217], protein–glycopeptide interaction [218], carbohydrate–ion interaction [219], and carbohydrate–water interaction [220]. …”