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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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List of residues selected by a consensus of the three best performing programs (Discotope, Ellipro and Epitopia) for each selected FMDV structure compared to locations of known antigenic sites of all serotypes.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.
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pone-0061122-g007: List of residues selected by a consensus of the three best performing programs (Discotope, Ellipro and Epitopia) for each selected FMDV structure compared to locations of known antigenic sites of all serotypes.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.

Mentions: To investigate the potential of using a consensus approach to predict novel epitopes the results for the three best performing programs in terms of average probability excess were selected (Epitopia, Ellipro and Discotope - see section above). The residues that were predicted to be antigenic by a consensus of all three programs on the selected structures were tabulated and compared to the known antigenic residues described previously (see Figure 7). Figure 2(g) indicates, as expected, that the sensitivity of such an approach is limited, however the significantly (P<0.01) increased accuracy obtained over any individual program (except the poorly performing program, BEPro P = 0.12) or using a consensus of 2 of the 3 programs (Figure 5(g)) validates the use of this approach. Additionally for the purpose of predicting novel epitopes using such a conservative approach is appropriate as the number of false positives should be as small as possible. It is also apparent that selecting the consensus results from any two of the best three methods gives an overall improvement in consistency, with all the sensitivity and specificity results in the right proportions (figure 2). Significant (P<0.01) improvements in the average probability excess were obtained compared to both Seppa and BEPro, and marginal, but not statistically significant, average probability excess 0.338 compared to 0.319 for the best performing program, Epitopia (Figure 2(f) and Figure 3). Whilst there was no improvement in precision or accuracy over any single program, it is possible that this approach may be useful for some applications.


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)

List of residues selected by a consensus of the three best performing programs (Discotope, Ellipro and Epitopia) for each selected FMDV structure compared to locations of known antigenic sites of all serotypes.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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0061122-g007: List of residues selected by a consensus of the three best performing programs (Discotope, Ellipro and Epitopia) for each selected FMDV structure compared to locations of known antigenic sites of all serotypes.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.
Mentions: To investigate the potential of using a consensus approach to predict novel epitopes the results for the three best performing programs in terms of average probability excess were selected (Epitopia, Ellipro and Discotope - see section above). The residues that were predicted to be antigenic by a consensus of all three programs on the selected structures were tabulated and compared to the known antigenic residues described previously (see Figure 7). Figure 2(g) indicates, as expected, that the sensitivity of such an approach is limited, however the significantly (P<0.01) increased accuracy obtained over any individual program (except the poorly performing program, BEPro P = 0.12) or using a consensus of 2 of the 3 programs (Figure 5(g)) validates the use of this approach. Additionally for the purpose of predicting novel epitopes using such a conservative approach is appropriate as the number of false positives should be as small as possible. It is also apparent that selecting the consensus results from any two of the best three methods gives an overall improvement in consistency, with all the sensitivity and specificity results in the right proportions (figure 2). Significant (P<0.01) improvements in the average probability excess were obtained compared to both Seppa and BEPro, and marginal, but not statistically significant, average probability excess 0.338 compared to 0.319 for the best performing program, Epitopia (Figure 2(f) and Figure 3). Whilst there was no improvement in precision or accuracy over any single program, it is possible that this approach may be useful for some applications.

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