An Approach For Identifying The Critical Amino Acid Residues On Binding Site Of GPIbα And VWF-Al Domain Through Molecular Dynamics Simulation

As a crucial step in a cascade of adhesion and signaling events in physiologicalhemostatic process, blood platelet adhesion to subendothelium of injured blood vessels isinitiated by interaction of platelet glycoprotein Ibα (GPIbα) with its ligand von Willebrandfactor (vWF). Under pathological conditions, this interaction can lead to thrombosis, anaccurate complication causing heart attack and stroke. Gain-of-function mutations in GPIba(e.g. M239V) occur in patients with platelet-type von Willebrand disease (vWD) and thencontribute to an abnormally high-affinity binding of platelets to vWF [3,4]. The patients sufferfrom bleeding disorders, which are increased with ristocetin-induced platelet aggregation andcharacterized by intermittent thrombo-cytopenia and absent high molecular weight forms ofplasma vWF.Based on the significant role in thrombosis, GPIb a becomes a noteworthy target forantibodies and antithrombotic drugs. Therefore, determine the key residues which regulate theaffinity between GPIb a and A1, attracting widespread attention and research for a long time.Mapping the key residues between biological molecules with mutagenesis experiments isan essential topic but usually expensive, time-consuming and blind. By molecular dynamicssimulation, we can observe the conformation of the protein complex evolution andcorresponding details of atomic motion in different temperature and pressure conditions, thenget the functional implications. Here, we introduced the residue interaction index (RII) basedon we newly developed molecular dynamics simulation, make use of H-bond or salt bridgesurvival rate to identify the key residues. We studied the residues and interation betweenGPIbα and vWF-A1through molecular dynamics simulation using RII, found21residues ofon the surface of GPIbα and21residues of on the surface of A1may participated theinteraction between GPIbα and A1serionsly. In these residues, a total of20residues (10inGPIbα,10in the A1) have been confirmed by mutation experiments, accounted for74%ofall confirmed residues. Another newly discovered22residues still need confirmation inmutation experiments. These hints: the computer strategy proposed in this paper have strongpotential to forecast key residues on the surface of the complex. The present computational procedure proposed by us can be used to forecast andindentify key residues in ligand-receptor interaction, provide guidance for monoclonalmolecular drug design. Exciting, not only the present results were in good agreement withprevious mutagenesis experiment data, but also found some residues may be important, butremains to be further confirmd, meaning a wide application prospect of our novelcomputational procedure on researches of molecular of basis of ligand-receptor interactions.