Conformational preferences of a peptide corresponding to the major antigenic determinant of foot-and-mouth disease virus: implications for peptide-vaccine approaches.
The conformational preferences in solution of a peptide corresponding to the GH loop of the VP1 capsid protein from the foot-and-mouth disease virus were examined by proton nuclear magnetic resonance and circular dichroism. The GH loop is the major antigenic determinant of the virus and participates in cell attachment through an integrin-like Arg-Gly-Asp sequence. The synthetic peptide, corresponding to residues Gly132 to Ser162 of the VP1 capsid protein of the serotype O, is largely disordered in aqueous solution as shown by the absence of long- and medium-range NOE contacts and by random-like chemical shifts values. Helical contents in aqueous solution were estimated to be less than 10%, as determined by extrapolation of trifluoroethanol titration from CD measurements, in good agreement with estimations from NMR experiments. In the presence of 40% trifluoroethanol an alpha-helix, flanked by two proline residues between Asn12 (Asn143 in the intact protein) and Leu28 (159), is induced. This contrasts with the 3(10) helix observed between residues Leu148 and Val155 in the crystal structure of the dithiothreitol-reduced virus, indicating that the cosolvent does not stabilize a residual, low-populated structure, similar to that in the intact virus. Several algorithms also fail to predict the structure found in the intact virus because these are based mainly on local sequence information. The lack of structure of the peptide in aqueous solution strongly suggests that the conformational determinants sufficient for the structure stabilization of this highly immunogenic antigen are mostly dictated by interactions of the loop with other regions of the virus structure, and do not arise from local amino acid sequence information. The ability of designed GH-VP1 peptides to neutralize anti-virus antibodies is likely to arise from antibody-induced conformation of the peptide and its application as peptide vaccines is not straightforward. Similarly, insertion of these peptides in carriers or macromolecular assemblies as vaccine vectors would depend on the conformation adopted at the insertion site and its success cannot be predicted.
de Prat-Gay
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Departamento de Bioquimica Medica, Universidade Federal do Rio de Janeiro, Cidade Universitaria, Brazil.
D000465:Algorithms; D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000737:chemistry* / Q000276:immunology; D005537:Aphthovirus / Q000276:immunology*; D002213:Capsid / Q000737:chemistry* / Q000276:immunology; D036022:Capsid Proteins; D002942:Circular Dichroism; D003553:Cystine / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012984:Software; D012996:Solutions; D012997:Solvents; D014270:Trifluoroethanol; D014765:Viral Vaccines; D014867:Water
D000956:Antigens, Viral; D036022:Capsid Proteins; D000939:Epitopes; D010446:Peptide Fragments; D012996:Solutions; D012997:Solvents; D014765:Viral Vaccines; D014867:Water; D003553:Cystine; D014270:Trifluoroethanol