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Evaluation and use of in-silico structure-based epitope prediction with foot-and-mouth disease virus.

Borley DW, Mahapatra M, Paton DJ, Esnouf RM, Stuart DI, Fry EE - PLoS ONE (2013)

Bottom Line: Individually any one algorithm performed rather poorly (three performing better than the other two) suggesting that there may be value in developing virus-specific software.The consensus results identified novel residues as potential epitopes on more than one serotype.These include residues 190-192 of VP2 (not previously determined to be antigenic), residues 69-71 and 193-197 of VP3 spanning the pentamer-pentamer interface, and another region incorporating residues 83, 84 and 169-174 of VP1 (all only previously experimentally defined on serotype A).

View Article: PubMed Central - PubMed

Affiliation: The Pirbright Institute, Pirbright, United Kingdom. daryl.borley@pirbright.ac.uk

ABSTRACT
Understanding virus antigenicity is of fundamental importance for the development of better, more cross-reactive vaccines. However, as far as we are aware, no systematic work has yet been conducted using the 3D structure of a virus to identify novel epitopes. Therefore we have extended several existing structural prediction algorithms to build a method for identifying epitopes on the appropriate outer surface of intact virus capsids (which are structurally different from globular proteins in both shape and arrangement of multiple repeated elements) and applied it here as a proof of principle concept to the capsid of foot-and-mouth disease virus (FMDV). We have analysed how reliably several freely available structure-based B cell epitope prediction programs can identify already known viral epitopes of FMDV in the context of the viral capsid. To do this we constructed a simple objective metric to measure the sensitivity and discrimination of such algorithms. After optimising the parameters for five methods using an independent training set we used this measure to evaluate the methods. Individually any one algorithm performed rather poorly (three performing better than the other two) suggesting that there may be value in developing virus-specific software. Taking a very conservative approach requiring a consensus between all three top methods predicts a number of previously described antigenic residues as potential epitopes on more than one serotype of FMDV, consistent with experimental results. The consensus results identified novel residues as potential epitopes on more than one serotype. These include residues 190-192 of VP2 (not previously determined to be antigenic), residues 69-71 and 193-197 of VP3 spanning the pentamer-pentamer interface, and another region incorporating residues 83, 84 and 169-174 of VP1 (all only previously experimentally defined on serotype A). The computer programs needed to create a semi-automated procedure for carrying out this epitope prediction method are presented.

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A side-by-side comparison of the molecular surface of five reduced O1 Kaufbeuren protomers made using Pymol, with the molecular surface of neighbouring protomers at each two fold axis of symmetry shown as a light blue mesh (Schrödinger LLC).Protomer (a) shows the residues in the regions A–G from Figure 7 coloured accordingly mapped onto the molecular surface (white). Protomer (b) shows the location of all described epitopes in blue for each serotype used in the analyses. Protomer (c) is a pictorial representation of the sequence variability of residues between 105 serotype O virus capsid sequences and Protomer (d) is a representation of the sequence variability of residues between 255 capsid sequences from all 7 serotypes. Both (c) and (d) were constructed using the ESPRIPT program [63] as described in the methods, the coloring goes from green (most conserved) to red (least conserved). Those sites predicted by a consensus of all programs on three or more structures tend to be located at areas of variability both inter and intra-serotypically. Region VP3 69–71 (highlighted in red on (a) and (c)) is completely conserved within serotype O, however it appears to be highly divergent between serotypes. (e) is the average RMSD across the serotypes coloured from green (smallest) to red (largest). Blue indicates the GH loop, missing on all but one structure.
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pone-0061122-g008: A side-by-side comparison of the molecular surface of five reduced O1 Kaufbeuren protomers made using Pymol, with the molecular surface of neighbouring protomers at each two fold axis of symmetry shown as a light blue mesh (Schrödinger LLC).Protomer (a) shows the residues in the regions A–G from Figure 7 coloured accordingly mapped onto the molecular surface (white). Protomer (b) shows the location of all described epitopes in blue for each serotype used in the analyses. Protomer (c) is a pictorial representation of the sequence variability of residues between 105 serotype O virus capsid sequences and Protomer (d) is a representation of the sequence variability of residues between 255 capsid sequences from all 7 serotypes. Both (c) and (d) were constructed using the ESPRIPT program [63] as described in the methods, the coloring goes from green (most conserved) to red (least conserved). Those sites predicted by a consensus of all programs on three or more structures tend to be located at areas of variability both inter and intra-serotypically. Region VP3 69–71 (highlighted in red on (a) and (c)) is completely conserved within serotype O, however it appears to be highly divergent between serotypes. (e) is the average RMSD across the serotypes coloured from green (smallest) to red (largest). Blue indicates the GH loop, missing on all but one structure.

Mentions: Those residues coloured red are an already known epitope on at least one serotype of FMDV, those in blue are adjacent to a known epitope of FMDV. Regions A–G are predicted to be antigenic on the majority of the serotypes tested and are coloured the same on Figures 8 and 9. The remaining residues are coloured grey, as Figures 8 and 9. Note that the SAT-1 virus VP1 has a incorporated several additional residues into the G–H loop and the A serotype also aligns slightly differently to the O and C structures, therefore the numbering is different in region C as they are aligned according to position on structure. All other residues are in approximately the same location relative to each other.


Evaluation and use of in-silico structure-based epitope prediction with foot-and-mouth disease virus.

Borley DW, Mahapatra M, Paton DJ, Esnouf RM, Stuart DI, Fry EE - PLoS ONE (2013)

A side-by-side comparison of the molecular surface of five reduced O1 Kaufbeuren protomers made using Pymol, with the molecular surface of neighbouring protomers at each two fold axis of symmetry shown as a light blue mesh (Schrödinger LLC).Protomer (a) shows the residues in the regions A–G from Figure 7 coloured accordingly mapped onto the molecular surface (white). Protomer (b) shows the location of all described epitopes in blue for each serotype used in the analyses. Protomer (c) is a pictorial representation of the sequence variability of residues between 105 serotype O virus capsid sequences and Protomer (d) is a representation of the sequence variability of residues between 255 capsid sequences from all 7 serotypes. Both (c) and (d) were constructed using the ESPRIPT program [63] as described in the methods, the coloring goes from green (most conserved) to red (least conserved). Those sites predicted by a consensus of all programs on three or more structures tend to be located at areas of variability both inter and intra-serotypically. Region VP3 69–71 (highlighted in red on (a) and (c)) is completely conserved within serotype O, however it appears to be highly divergent between serotypes. (e) is the average RMSD across the serotypes coloured from green (smallest) to red (largest). Blue indicates the GH loop, missing on all but one structure.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646828&req=5

pone-0061122-g008: A side-by-side comparison of the molecular surface of five reduced O1 Kaufbeuren protomers made using Pymol, with the molecular surface of neighbouring protomers at each two fold axis of symmetry shown as a light blue mesh (Schrödinger LLC).Protomer (a) shows the residues in the regions A–G from Figure 7 coloured accordingly mapped onto the molecular surface (white). Protomer (b) shows the location of all described epitopes in blue for each serotype used in the analyses. Protomer (c) is a pictorial representation of the sequence variability of residues between 105 serotype O virus capsid sequences and Protomer (d) is a representation of the sequence variability of residues between 255 capsid sequences from all 7 serotypes. Both (c) and (d) were constructed using the ESPRIPT program [63] as described in the methods, the coloring goes from green (most conserved) to red (least conserved). Those sites predicted by a consensus of all programs on three or more structures tend to be located at areas of variability both inter and intra-serotypically. Region VP3 69–71 (highlighted in red on (a) and (c)) is completely conserved within serotype O, however it appears to be highly divergent between serotypes. (e) is the average RMSD across the serotypes coloured from green (smallest) to red (largest). Blue indicates the GH loop, missing on all but one structure.
Mentions: Those residues coloured red are an already known epitope on at least one serotype of FMDV, those in blue are adjacent to a known epitope of FMDV. Regions A–G are predicted to be antigenic on the majority of the serotypes tested and are coloured the same on Figures 8 and 9. The remaining residues are coloured grey, as Figures 8 and 9. Note that the SAT-1 virus VP1 has a incorporated several additional residues into the G–H loop and the A serotype also aligns slightly differently to the O and C structures, therefore the numbering is different in region C as they are aligned according to position on structure. All other residues are in approximately the same location relative to each other.

Bottom Line: Individually any one algorithm performed rather poorly (three performing better than the other two) suggesting that there may be value in developing virus-specific software.The consensus results identified novel residues as potential epitopes on more than one serotype.These include residues 190-192 of VP2 (not previously determined to be antigenic), residues 69-71 and 193-197 of VP3 spanning the pentamer-pentamer interface, and another region incorporating residues 83, 84 and 169-174 of VP1 (all only previously experimentally defined on serotype A).

View Article: PubMed Central - PubMed

Affiliation: The Pirbright Institute, Pirbright, United Kingdom. daryl.borley@pirbright.ac.uk

ABSTRACT
Understanding virus antigenicity is of fundamental importance for the development of better, more cross-reactive vaccines. However, as far as we are aware, no systematic work has yet been conducted using the 3D structure of a virus to identify novel epitopes. Therefore we have extended several existing structural prediction algorithms to build a method for identifying epitopes on the appropriate outer surface of intact virus capsids (which are structurally different from globular proteins in both shape and arrangement of multiple repeated elements) and applied it here as a proof of principle concept to the capsid of foot-and-mouth disease virus (FMDV). We have analysed how reliably several freely available structure-based B cell epitope prediction programs can identify already known viral epitopes of FMDV in the context of the viral capsid. To do this we constructed a simple objective metric to measure the sensitivity and discrimination of such algorithms. After optimising the parameters for five methods using an independent training set we used this measure to evaluate the methods. Individually any one algorithm performed rather poorly (three performing better than the other two) suggesting that there may be value in developing virus-specific software. Taking a very conservative approach requiring a consensus between all three top methods predicts a number of previously described antigenic residues as potential epitopes on more than one serotype of FMDV, consistent with experimental results. The consensus results identified novel residues as potential epitopes on more than one serotype. These include residues 190-192 of VP2 (not previously determined to be antigenic), residues 69-71 and 193-197 of VP3 spanning the pentamer-pentamer interface, and another region incorporating residues 83, 84 and 169-174 of VP1 (all only previously experimentally defined on serotype A). The computer programs needed to create a semi-automated procedure for carrying out this epitope prediction method are presented.

Show MeSH
Related in: MedlinePlus