Molecular Simulation Of Glycoprotein VI With Antithrombotic Antibody10B12

As the most common cause of death in the developed countris, acute arterial thrombosiscan lead to fatal myocardial infarction (heart attack) and stroke. Adhesion of platelets to thesite of vascular injury is a key process for physiological hemostasis and pathologicalthrombosis. Platelet adhension is a multi-step cascade including tethering, rolling and firmadhesion, which are mediated by various interactions between distinct receptors and ligands.The development of monoclonal antibodies technique has evolved into a mainstay oftherapeutic options for patients with autoimmune, inflammatory, tumorous and cardiovasculardiseases. However, the antibody acquired by the hybridoma and the antibody phage displaytechnique often need to be further reformation to improve their clinical potential. Thus, theprecise identification and lacation of antigen epitope and antibody complement is one of thekey procedure.Mapping paratope to epitope with mutagenesis experiments, a traditional route such as x-ray analyses of crystals, nuclear magnetic resonance in researches of these antithromboticmonoclonal antibodies, is usually expensive and time-consuming. So, the researcher usedcomputer with rigid and flexible docking in the design of antibody. It is not enough to obtainthe stability and strength or other information only from a limited number of staticconfiguration.Binding of Immunoglobulin(Ig)-like receptor GPVI to collagen is essential for plateletactivation and sequent stable adhesion. Of various antithrombotic monoclonal antibodiestargeting GPVI,10B12is a potent one to inhibit the interaction between GPVI and collagen.Here, a novel computational procedure, which combines with homology modeling, rigid bodydocking and free molecular dynamics simulations, was proposed to identify key paratoperesidues on10B12and their partners on GPVI. During processes of the system equilibriumand free molecular dynamics simulations, the formation and evolution of hydrogen bondingand salt bridge on the binding sites of GPVI and10B12were observed and analyzed by VMD. Then a residue interaction index, which is scored with the survival ratios of salt bridges and/orhydrogen bonds involved in interaction of a residue to other(s), was introduced to used as acriterion of the residue’s role in interaction between receptor and ligand. With hypothesis thatthe residue its RII larger than0.5is important, all key epitope residues confirmed viamutagenesis experiments were shown in our predicted results, and7of8noncritical residuesconfirmed by experiments were excluded. The results demonstrated that this novel approachis useful for computationally identifying the key residues of antibody such as10B12boundwith GPVI. The computer strategy presented here should find its application in the traditionalmutagenesis experiments and the computer-aided antibody drugs design.