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Role of antibody paratope conformational flexibility in the manifestation of molecular mimicry.

ABSTRACT: Molecular mimicry is a recurrent theme in host defense processes. The correlation of functional mimicry with the structural features of the antibody paratope has been investigated, addressing the consequences of mimicry in host immune mechanisms. Two anti-mannopyranoside antibodies, 1H7 and 2D10, representing the possible extremes of the recognition spectrum with regard to peptide-carbohydrate mimicry were examined. Crystallographic and molecular dynamics simulation analyses established correlation between the antibody flexibility and the manifestation of mimicry. It was evident that monoclonal antibody (mAb) 1H7, which has a narrow specificity in favor of the immunizing antigen, exhibited structural invariance. On the other hand, the antigen-combining site of 2D10, the mimicry-recognizing antibody, showed substantial divergence in the complementarity determining region loops. The docking of mannopyranoside within the antibody paratope revealed multiple modes of binding of the carbohydrate antigen in mAb 2D10 vis à vis single docking mode in mAb 1H7, which overlapped with the common monosaccharide binding site defined in anti-carbohydrate antibodies. The presence of additional antigen binding modes is perhaps reflective of the utilization of conformational flexibility in molecular mimicry. A relatively broader recognition repertoire--attributable to paratope flexibility--may facilitate the recognition of altered antigens of invading pathogens while the antibodies with narrow recognition specificity maintain the fidelity of the response.

SUBMITTER: Krishnan L

PROVIDER: S-EPMC2212675 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Role of antibody paratope conformational flexibility in the manifestation of molecular mimicry.

Krishnan Lavanya L Sahni Gaurav G Kaur Kanwal J KJ Salunke Dinakar M DM

Biophysical journal 20071121 4

Molecular mimicry is a recurrent theme in host defense processes. The correlation of functional mimicry with the structural features of the antibody paratope has been investigated, addressing the consequences of mimicry in host immune mechanisms. Two anti-mannopyranoside antibodies, 1H7 and 2D10, representing the possible extremes of the recognition spectrum with regard to peptide-carbohydrate mimicry were examined. Crystallographic and molecular dynamics simulation analyses established correlat ...[more]

PMID: 18032557

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Project description:Binding of platelet receptor glycoprotein Ibα (GPIbα) to the A1 domain of von Willebrand factor (vWF) is a critical step in both physiologic hemostasis and pathologic thrombosis, for initiating platelet adhesion to subendothelium of blood vessels at sites of vascular injury. Gain-of-function mutations in GPIbα contribute to an abnormally high-affinity binding of platelets to vWF and can lead to thrombosis, an accurate complication causing heart attack and stroke. Of various antithrombotic monoclonal antibodies (mAbs) targeting human GPIbα, 6B4 is a potent one to inhibit the interaction between GPIbα and vWF-A1 under static and flow conditions. Mapping paratope to epitope with mutagenesis experiments, a traditional route in researches of these antithrombotic mAbs, is usually expensive and time-consuming. Here, we suggested a novel computational procedure, which combines with homology modeling, rigid body docking, free and steered molecular dynamics (MD) simulations, to identify key paratope residues on 6B4 and their partners on GPIbα, with hypothesis that the stable hydrogen bonds and salt bridges are the important linkers between paratope and epitope residues. Based on a best constructed model of 6B4 bound with GPIbα, the survival ratios and rupture times of all detected hydrogen bonds and salt bridges in binding site were examined via free and steered MD simulations and regarded as indices of thermal and mechanical stabilizations of the bonds, respectively. Five principal paratope residues with their partners were predicted with their high survival ratios and/or long rupture times of involved hydrogen bonds, or with their hydrogen bond stabilization indices ranked in top 5. Exciting, the present results were in good agreement with previous mutagenesis experiment data, meaning a wide application prospect of our novel computational procedure on researches of molecular of basis of ligand-receptor interactions, various antithrombotic mAbs and other antibodies as well as theoretically design of biomolecular drugs.

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Role of antibody paratope conformational flexibility in the manifestation of molecular mimicry.

Publications

Role of antibody paratope conformational flexibility in the manifestation of molecular mimicry.

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