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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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Building the multimer.(a) Schematic depiction of the foot and mouth disease icosahedral capsid with the individual virion peptides labelled. A viral subunit is coloured as per the standard colouring sytem; VP1 is blue, VP2 is in green and VP3 is red. (b) Schematic depiction of the of the same structure as (a) with the four subunits selected to make the multimer labelled as chains 1–4 (highlighted in red). These four protomers form the multimeric structure that was used in the analysis.
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pone-0061122-g001: Building the multimer.(a) Schematic depiction of the foot and mouth disease icosahedral capsid with the individual virion peptides labelled. A viral subunit is coloured as per the standard colouring sytem; VP1 is blue, VP2 is in green and VP3 is red. (b) Schematic depiction of the of the same structure as (a) with the four subunits selected to make the multimer labelled as chains 1–4 (highlighted in red). These four protomers form the multimeric structure that was used in the analysis.

Mentions: FMDV is a small icosahedral virus 30 nm in diameter, comprising 60 copies of each of the 4 structural proteins VP1-4 (see Figure 1(a)). VP1, 2 and 3 constitute the surface of the virus and are composed of 8 anti-parallel β strands linked by loops to form a β barrel. VP4 is much smaller, internal and has little secondary structure [6]. The highly mobile VP1 G-H loop protrudes from the surface of the virus and contains the arginine-glycine-aspartic acid (RGD) motif responsible for attachment to host integrins [7]. This loop is also antigenic on all serotypes of FMDV. Due to its disorganised (flexible) nature this loop is absent from many of the crystallographic structures reported, although it has been visualised when stabilised by chemical reduction [8] or bound to monoclonal antibody [9].


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)

Building the multimer.(a) Schematic depiction of the foot and mouth disease icosahedral capsid with the individual virion peptides labelled. A viral subunit is coloured as per the standard colouring sytem; VP1 is blue, VP2 is in green and VP3 is red. (b) Schematic depiction of the of the same structure as (a) with the four subunits selected to make the multimer labelled as chains 1–4 (highlighted in red). These four protomers form the multimeric structure that was used in the analysis.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0061122-g001: Building the multimer.(a) Schematic depiction of the foot and mouth disease icosahedral capsid with the individual virion peptides labelled. A viral subunit is coloured as per the standard colouring sytem; VP1 is blue, VP2 is in green and VP3 is red. (b) Schematic depiction of the of the same structure as (a) with the four subunits selected to make the multimer labelled as chains 1–4 (highlighted in red). These four protomers form the multimeric structure that was used in the analysis.
Mentions: FMDV is a small icosahedral virus 30 nm in diameter, comprising 60 copies of each of the 4 structural proteins VP1-4 (see Figure 1(a)). VP1, 2 and 3 constitute the surface of the virus and are composed of 8 anti-parallel β strands linked by loops to form a β barrel. VP4 is much smaller, internal and has little secondary structure [6]. The highly mobile VP1 G-H loop protrudes from the surface of the virus and contains the arginine-glycine-aspartic acid (RGD) motif responsible for attachment to host integrins [7]. This loop is also antigenic on all serotypes of FMDV. Due to its disorganised (flexible) nature this loop is absent from many of the crystallographic structures reported, although it has been visualised when stabilised by chemical reduction [8] or bound to monoclonal antibody [9].

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