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Predicción de unión de péptidos de MSA-2 y AMA-1 de Plasmodium falciparum al HLA clase II
Peptide binding prediction for MSA-2 and AMA-1 from Plasmodium falciparum to HLA Class II
Javier Rodríguez
Autor para correspondencia
grupoinsight2025@yahoo.es

Carrera 79, número 51-16 Sur, Apartamento 102, Bogotá, Colombia.
, Pedro Bernal, Catalina Correa, Signed Prieto, Luisa Benítez, Sarith Viteri, Germán Puerta, Diana Muñoz, Ingrid Rojas, Yolanda Soracipa
Grupo Insight, Universidad Militar Nueva Granada. Bogotá, Colombia
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0005">INTRODUCCI&#211;N</span><p id="p0005" class="elsevierStylePara elsevierViewall">Actualmente&#44; la malaria representa la enfermedad parasitaria de mayor importancia mundial al generar cerca de 500 millones de casos&#47;a&#241;o en todo el mundo y cerca de 3 millones de muertes s&#243;lo en &#193;frica<a class="elsevierStyleCrossRefs" href="#bb0005"><span class="elsevierStyleSup">&#40;1&#44;2&#41;</span></a>&#46; Dado que las estrategias cl&#225;sicas de control han fallado&#44; se han desarrollado m&#250;ltiples trabajos dirigidos al conocimiento del proceso de invasi&#243;n al humano&#44; para el desarrollo de vacunas&#46; Los procesos impl&#237;citos a dicha invasi&#243;n est&#225;n mediados por interacciones receptor ligando espec&#237;ficas&#46;</p><p id="p0010" class="elsevierStylePara elsevierViewall">La segunda de las proteinas principales de la superficie del merozoito del Plasmodium falciparum es conocida como MSA-2&#44; y es una glicoprote&#237;na de 35&#177;56<span class="elsevierStyleHsp" style=""></span>kDa<a class="elsevierStyleCrossRefs" href="#bb0015"><span class="elsevierStyleSup">&#40;3&#44;4&#41;</span></a>&#44; que se expresa doce horas antes de la invasi&#243;n del merozoito&#44; y presenta su m&#225;xima concentraci&#243;n 42 horas despu&#233;s<a class="elsevierStyleCrossRefs" href="#bb0025"><span class="elsevierStyleSup">&#40;5&#44;6&#41;</span></a>&#46; Hace parte del grupo de ant&#237;genos reconocidos por anticuerpos que aglutinan merozoitos<a class="elsevierStyleCrossRefs" href="#bb0035"><span class="elsevierStyleSup">&#40;7&#44;8&#41;</span></a> y se ha encontrado que anticuerpos de MSA-2 inhiben invasi&#243;n de una forma dosis-dependiente <span class="elsevierStyleItalic">in</span> vitro<a class="elsevierStyleCrossRefs" href="#bb0045"><span class="elsevierStyleSup">&#40;9-11&#41;</span></a>&#46; Por otro lado&#44; Plasmodium falciparum AMA-1 es una prote&#237;na de 83<span class="elsevierStyleHsp" style=""></span>kDa caracterizada por una alta conservaci&#243;n en la transmembrana menor de la mol&#233;cula&#46; Dentro de su estructura&#44; tiene un ectodominio putativo&#44; el cual contiene 16 cisteinas&#44; as&#237; como tres subdominios de 19&#44; 13 y 13<span class="elsevierStyleHsp" style=""></span>kDa&#44; respectivamente<a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">&#40;12&#41;</span></a>&#46; En el proceso de ruptura del esquizonte&#44; esta prote&#237;na se asocia con el complejo apical y se desplaza a la superficie del merozoito<a class="elsevierStyleCrossRef" href="#bb0065"><span class="elsevierStyleSup">&#40;13&#41;</span></a>&#46; La funci&#243;n biol&#243;gica de la AMA-1 es desconocida&#44; sin embargo&#44; podr&#237;a tratarse de una prote&#237;na de uni&#243;n eritrocitaria&#46;</p><p id="p0015" class="elsevierStylePara elsevierViewall">El HLA&#44; o ant&#237;geno leucocitario humano es un complejo prote&#237;nico que tiene como funci&#243;n la presentaci&#243;n de ant&#237;genos a las c&#233;lulas T para la activaci&#243;n de la respuesta inmune&#46; Los ant&#237;genos asociados al HLA clase I son reconocidos por las c&#233;lulas T CD8<span class="elsevierStyleSup">&#43;</span>&#44; mientras que los asociados al HLA clase II son reconocidos por las c&#233;lulas T cooperadoras CD4<span class="elsevierStyleHsp" style=""></span>&#43;<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">&#40;14&#41;</span></a>&#46; El HLA clase II est&#225; compuesto por dos cadenas polim&#243;rficas y su regi&#243;n central est&#225; formado por los dominios &#945;1 y &#946;1 de las dos cadenas&#44; conformando una hendidura que constituye la regi&#243;n de uni&#243;n a los ant&#237;genos<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">&#40;15&#41;</span></a>&#46; Al estar abierta en sus extremos<a class="elsevierStyleCrossRefs" href="#bb0080"><span class="elsevierStyleSup">&#40;16-19&#41;</span></a>&#44; a ella se unen p&#233;ptidos con tama&#241;os muy variables&#44; que oscilan entre 13 y 16 amino&#225;cidos<a class="elsevierStyleCrossRefs" href="#bb0100"><span class="elsevierStyleSup">&#40;20-23&#41;</span></a>&#46; Sin embargo estudios experimentales del fen&#243;meno de uni&#243;n han sugerido que s&#243;lo una regi&#243;n central compuesta por nueve amino&#225;cidos es fundamental en este proceso de uni&#243;n<a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">&#40;24&#41;</span></a>&#46; Adicionalmente se ha encontrado una alta frecuencia de aparici&#243;n de grupos de amino&#225;cidos en posiciones espec&#237;ficas&#44; posiciones de anclaje&#44; denominados motivos de uni&#243;n<a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">&#40;25&#41;</span></a>&#44; determinados a partir de grupos seleccionados&#44; tales como librer&#237;as M13 de p&#233;ptidos presentados&#46;</p><p id="p0020" class="elsevierStylePara elsevierViewall">Dado que el HLA clase II es esencial en el reconocimiento de organismos ajenos&#44; resulta de gran utilidad para el desarrollo de vacunas determinar si existen p&#233;ptidos de las prote&#237;nas de MSA-2 y AMA-1 que puedan ser reconocidos por dicha mol&#233;cula&#46; Recientemente&#44; Rodr&#237;guez<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">&#40;26&#41;</span></a> desarroll&#243; una teor&#237;a para la predicci&#243;n de p&#233;ptidos a la regi&#243;n central del HLA clase II&#44; con base en las teor&#237;as de probabilidad&#44; combinatoria y entrop&#237;a&#46; En dicho trabajo&#44; las secuencias pept&#237;dicas fueron estudiadas realizando una analog&#237;a con los macroestados de la mec&#225;nica estad&#237;stica&#44; los cuales pueden caracterizarse por m&#250;ltiples particularidades&#44; como las m&#250;ltiples posibles formas de organizaci&#243;n de las mol&#233;culas de un gas<a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">&#40;27&#41;</span></a>&#44; que cumplen con ciertas condiciones generales que les permiten ser incluidas dentro de un mismo macroestado&#46; Esta teor&#237;a se bas&#243; en un experimento mental f&#237;sico y experimental en el cual se conceptualiz&#243; la regi&#243;n central de uni&#243;n como un fen&#243;meno probabil&#237;stico&#44; en el cual estaban implicados un n&#250;mero finito de amino&#225;cidos que pod&#237;an tomar cada lugar&#44; encontrando que ciertos lugares ten&#237;an una mayor probabilidad de presentar ciertos grupos de amino&#225;cidos respecto a otros&#44; en el caso de unirse al HLA clase II&#46; De este modo se realiz&#243; la suposici&#243;n de lo que ocurrir&#237;a en el caso de encontrar un p&#233;ptido con todos los amino&#225;cidos iguales&#44; as&#237; como un p&#233;ptido que presentara todos sus amino&#225;cidos diferentes&#44; encontrando que los p&#233;ptidos de uni&#243;n se caracterizan por ciertas repeticiones y diferencias que pod&#237;an cuantificarse al agrupar los amino&#225;cidos de acuerdo a grupos y caracter&#237;sticas especificas&#44; con base en las leyes de probabilidad y combinatoria&#46; Al tratarse de un fen&#243;meno probabil&#237;stico&#44; la autoorganizaci&#243;n general del sistema pod&#237;a ser evaluado con las leyes de la entrop&#237;a&#44; encontrando diferencias cuantitativas en la relaci&#243;n S&#47;k en el fen&#243;meno de uni&#243;n respecto al de no uni&#243;n&#46; De este modo&#44; se caracterizaron matem&#225;ticamente 161 p&#233;ptidos&#44; con una eficacia del 100&#37; partiendo de p&#233;ptidos te&#243;ricos&#44; sint&#233;ticos&#44; naturales y promiscuos&#44; tanto de uni&#243;n como de no uni&#243;n&#46; En un trabajo previo&#44; en proceso de evaluaci&#243;n se aplic&#243; esta misma metodolog&#237;a a dos prote&#237;nas el HER2&#47;neu y la API m1&#44; y se comprobaron los resultados con los hallazgos experimentales de estas prote&#237;nas y se compar&#243; el desempe&#241;o con los resultados de los m&#233;todos de predicci&#243;n de p&#233;ptidos disponibles en l&#237;nea de mayor cobertura al&#233;lica&#44; obteniendo los mayores valores para la sensibilidad&#44; valor predictivo positivo y exactitud&#46;</p><p id="p0025" class="elsevierStylePara elsevierViewall">Las leyes de probabilidad permiten la cuantificaci&#243;n de la posibilidad de la ocurrencia de un evento<a class="elsevierStyleCrossRefs" href="#bb0140"><span class="elsevierStyleSup">&#40;28-31&#41;</span></a>&#46; Al estudiar la organizaci&#243;n de amino&#225;cidos para la construcci&#243;n de un p&#233;ptido como un fen&#243;meno probabil&#237;stico&#44; es posible realizar cuantificaciones que dan cuenta de la combinaci&#243;n de los amino&#225;cidos en las secuencias&#46; Por otro lado&#44; la entrop&#237;a es un concepto que ha recibido varias interpretaciones<a class="elsevierStyleCrossRefs" href="#bb0135"><span class="elsevierStyleSup">&#40;27&#44;32-34&#41;</span></a>&#46; Boltzmann enunci&#243; la f&#243;rmula de la entrop&#237;a equiprobable&#44; la cual se enuncia en t&#233;rminos del n&#250;mero de microestados de un sistema en equilibrio<a class="elsevierStyleCrossRefs" href="#bb0160"><span class="elsevierStyleSup">&#40;32&#44;33&#41;</span></a>&#46; Siguiendo la teor&#237;a desarrollada por Rodr&#237;guez<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">&#40;26&#41;</span></a>&#44; haciendo una analog&#237;a con los microestados de la mec&#225;nica estad&#237;stica&#44; cada conjunto de amino&#225;cidos que conforma las secuencias de los p&#233;ptidos&#44; pueden analizarse mediante la ecuaci&#243;n de Boltzmann&#44; para cuantificar el fen&#243;meno de uni&#243;n de los p&#233;ptidos de las prote&#237;nas antig&#233;nicas&#46;</p><p id="p0030" class="elsevierStylePara elsevierViewall">En la presente investigaci&#243;n se aplicar&#225; la teor&#237;a de predicci&#243;n de uni&#243;n de p&#233;ptidos a la regi&#243;n central del HLA clase II&#44; a los p&#233;ptidos non&#225;meros de MSA-2&#44; y la prote&#237;na AMA-1&#44; y a los 492 p&#233;ptidos non&#225;meros sobrelapados de tres prote&#237;nas te&#243;ricas&#44; de 500 amino&#225;cidos cada una&#46;</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0010">DEFINICIONES</span><p id="p0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Macroestado&#58;</span> conjunto de secuencias que presentan alta uni&#243;n o no uni&#243;n al HLA clase II&#44; por lo tanto existen dos clases de macroestados&#44; asociados a cada una de estas condiciones espec&#237;ficas&#46;</p><p id="p0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Microestado&#58;</span> Toda secuencia espec&#237;fica de nueve amino&#225;cidos&#46;</p><p id="p0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Tipo de secuencia&#58;</span> Microestados que presenten el mismo valor en su combinatoria y su evaluaci&#243;n con los criterios definidos&#46;</p><p id="p0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Probabilidad Laplaciana&#58;</span> La probabilidad de un tipo de secuencia A es definida como la cantidad de microestados Na asociados a este tipo de secuencia dividida entre el total de posibles microestados N<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">&#40;29&#41;</span></a>&#46; Ver <a class="elsevierStyleCrossRef" href="#fo0005">ecuaci&#243;n 1</a>&#46;</p><p id="p0055" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="fo0005"></elsevierMultimedia></p><p id="p0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Ley combinatoria para determinar la cantidad de microestados</span> &#969;&#58; De acuerdo con la metodolog&#237;a desarrollada por Rodr&#237;guez<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">&#40;26&#41;</span></a>&#44; cada posici&#243;n del p&#233;ptido tiene asociada un n&#250;mero de posibles amino&#225;cidos&#46; Para calcular el n&#250;mero de posibles microestados asociados a un tipo de secuencia se multiplican los valores asociados a cada posici&#243;n&#44; que dependen del n&#250;mero de posibles amino&#225;cidos asociados a cada lugar&#44; los cuales a su vez est&#225;n determinados por el grupo al que pertenezcan y sus repeticiones en el tipo de secuencia<a class="elsevierStyleCrossRefs" href="#bb0150"><span class="elsevierStyleSup">&#40;30&#44;31&#41;</span></a>&#46; Para las cuantificaciones espec&#237;ficas ver tablas de criterios evaluadores y tablas de grupos de amino&#225;cidos de la teor&#237;a realizada&#46;</p><p id="p0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Entrop&#237;a&#58;</span> En un sistema con microestados equiprobables la entrop&#237;a se define de acuerdo con la <a class="elsevierStyleCrossRef" href="#fo0010">ecuaci&#243;n 2</a>&#58;</p><p id="p0075" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="fo0010"></elsevierMultimedia></p><p id="p0085" class="elsevierStylePara elsevierViewall">Donde k es igual a la constante de Boltzmann&#44; 1&#46;38x10<span class="elsevierStyleSup">-<span class="elsevierStyleHsp" style=""></span>23</span> &#40;J&#47;k&#41;&#44; &#969; los posibles microestados y S el valor de la entrop&#237;a<a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">&#40;27&#41;</span></a>&#46;</p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">MATERIAL Y METODO</span><p id="p0090" class="elsevierStylePara elsevierViewall">Inicialmente se determinaron los p&#233;ptidos non&#225;meros sobrelapados constituyentes de las 25 secuencias no sobrelapadas de 20 amino&#225;cidos de la prote&#237;na MSA-2&#44; y de las 31 secuencias de 20 amino&#225;cidos sobrelapados cada diez amino&#225;cidos de la prote&#237;na AMA-1&#44; as&#237; como los p&#233;ptidos non&#225;meros sobrelapados de tres prote&#237;nas te&#243;ricas compuestas por 500 residuos&#46; Posteriormente se aplic&#243; la metodolog&#237;a desarrollada por Rodr&#237;guez<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">&#40;26&#41;</span></a> para la determinaci&#243;n de su macroestado de uni&#243;n o no uni&#243;n&#46; Para ejemplificar la aplicaci&#243;n de la metodolog&#237;a a continuaci&#243;n se presenta un ejemplo para el p&#233;ptido non&#225;mero predicho de uni&#243;n por la teor&#237;a desarrollada FLPTGAFKA que pertenece al p&#233;ptido 20-mero de alta uni&#243;n 4325 de la prote&#237;na AMA-1&#46;</p><p id="p0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Paso 1&#58;</span> La primera posici&#243;n F tiene un valor de 7 pues pertenece al grupo 1 &#40;<a class="elsevierStyleCrossRef" href="#t0005">Tabla I</a>&#41;&#59; en la posici&#243;n dos a L se le otorga un valor de 6 pues pertenece al grupo 1 y el valor decrece por la aparici&#243;n previa de un amino&#225;cido del mismo grupo y diferente&#59; en la posici&#243;n tres a P se le otorga un valor de 4 pues pertenece al grupo 3&#59; a la siguiente posici&#243;n&#44; a T se le otorga un valor de 9 pues pertenece al grupo 2&#59; la siguiente posici&#243;n G toma un valor de 3&#44; pues pertenece al grupo 3 y el valor decrece por la aparici&#243;n previa de un amino&#225;cido del mismo grupo y diferente a G&#59; la siguiente posici&#243;n A toma un valor de 6&#44; pues pertenece al grupo de motivos para dicha posici&#243;n&#59; en la siguiente posici&#243;n la F toma un valor de 1&#44; pues el amino&#225;cido ya hab&#237;a aparecido&#44; la K toma un valor de 5&#44; dado que est&#225; dentro del grupo de amino&#225;cidos cargados&#59; finalmente&#44; en la &#250;ltima posici&#243;n la A toma un valor de 1 dado que dicho amino&#225;cido ya hab&#237;a aparecido&#46;</p><elsevierMultimedia ident="t0005"></elsevierMultimedia><p id="p0100" class="elsevierStylePara elsevierViewall">Para el paso dos se verifica que este p&#233;ptido no cumple ninguno de los criterios establecidos&#44; por lo tanto el n&#250;mero de microestados asociados es 136080&#44; la entrop&#237;a de 1&#44;63E-22&#44; y la relaci&#243;n S&#47;k de 11&#44;82&#44; por lo cual se realizan los pasos siguientes&#58;</p><p id="p0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Paso 3&#58;</span> La primera posici&#243;n F tiene un valor de 5 pues es Hidrof&#243;bico de alta uni&#243;n &#40;<a class="elsevierStyleCrossRef" href="#t0010">Tabla II</a>&#41;&#59; en la posici&#243;n dos a L se le otorga un valor de 5 pues pertenece al grupo 4&#44; en la posici&#243;n tres a P se le otorga un valor de 4 pues pertenece al grupo 4 y el valor decrece por la aparici&#243;n previa de un amino&#225;cido del mismo grupo&#59; en la siguiente posici&#243;n&#44; a T se le otorga un valor de 6 pues pertenece al grupo de Puentes de hidr&#243;geno&#59; la siguiente posici&#243;n G toma un valor de 3 pues pertenece al grupo 4 y el valor decrece por la aparici&#243;n previa de un amino&#225;cido del mismo grupo&#59; la siguiente posici&#243;n A&#41;toma un valor de 2&#44; pues pertenece al grupo 4 y el valor decrece por la aparici&#243;n previa de un amino&#225;cido del mismo grupo&#59; en la siguiente posici&#243;n la F toma un valor de 1&#44; pues el amino&#225;cido ya hab&#237;a aparecido&#59; la K toma un valor de 3&#44; dado que est&#225; dentro del grupo de cargados positivos&#59; finalmente la &#250;ltima posici&#243;n la A toma un valor de 1 dado que dicho amino&#225;cido ya hab&#237;a aparecido&#46;</p><elsevierMultimedia ident="t0010"></elsevierMultimedia><p id="p0110" class="elsevierStylePara elsevierViewall">Para el paso cuatro se verifica que este p&#233;ptido no cumple ninguno de los criterios establecidos por lo tanto el n&#250;mero de microestados asociados es 10800&#44; la entrop&#237;a de 1&#44;28E-22&#44; y la relaci&#243;n S&#47;k de 9&#44;28&#44; por lo tanto dicho p&#233;ptido pertenece al macroestado Uni&#243;n&#46;</p><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">Predicciones f&#237;sicas y matem&#225;ticas</span><p id="p0115" class="elsevierStylePara elsevierViewall">La predicci&#243;n te&#243;rica desarrollada por Rodr&#237;guez<a class="elsevierStyleCrossRef" href="#bb0130">&#40;26</a>&#41; se calcula con base en el rango de microestados y de entrop&#237;a asociado a la uni&#243;n&#44; determinando el n&#250;mero de microestados equivalentes y la configuraci&#243;n espec&#237;fica que deben tener los p&#233;ptidos de uni&#243;n al HLA clase II&#44; mediante el despeje de &#969; en la ecuaci&#243;n de Boltzmann &#40;<a class="elsevierStyleCrossRef" href="#fo0010">Ecuaci&#243;n 2</a>&#41;&#44; que es el n&#250;mero de microestados asociados a cada tipo de secuencia&#46; De este modo&#44; se realiza la deducci&#243;n f&#237;sica y matem&#225;tica de las secuencias de amino&#225;cidos que se unen&#44; <a class="elsevierStyleCrossRef" href="#fo0015">Ecuaci&#243;n 3</a>&#46;</p><p id="p0120" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="fo0015"></elsevierMultimedia></p><p id="p0130" class="elsevierStylePara elsevierViewall">Despu&#233;s&#44; con base en la <a class="elsevierStyleCrossRef" href="#fo0010">Ecuaci&#243;n 2</a>&#44; se despeja el valor de S&#47;k&#44; <a class="elsevierStyleCrossRef" href="#fo0020">Ecuaci&#243;n 4</a>&#46;</p><p id="p0135" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="fo0020"></elsevierMultimedia></p><p id="p0145" class="elsevierStylePara elsevierViewall">La proporci&#243;n S&#47;k permite predecir cuales son los valores de los p&#233;ptidos asociados al macroestado de uni&#243;n y cuales son los asociados al macroestado de no uni&#243;n&#46; De este modo se eval&#250;an las proporciones S&#47;k entre 8&#44;55 y 12&#44;8 para los primeros pasos y entre 6&#44;98 y 10&#44;5 para los &#250;ltimos pasos como relacionadas con el macroestado de uni&#243;n al HLA clase II de acuerdo con la teor&#237;a desarrollada previamente<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">&#40;26&#41;</span></a>&#46;</p></span></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">RESULTADOS</span><p id="p0150" class="elsevierStylePara elsevierViewall">De los 300 p&#233;ptidos non&#225;meros analizados para MSA-2&#44; 35 corresponden al macroestado de uni&#243;n&#44; 11&#46;6&#37; respecto a la totalidad&#44; mientras que 265 corresponden al macroestado de no uni&#243;n &#40;<a class="elsevierStyleCrossRef" href="#t0005">Tabla I</a>&#41;&#46; De los 377 p&#233;ptidos analizados de AMA-1&#44; 60 corresponden al macroestado de uni&#243;n&#44; 15&#46;91&#37; respecto a la totalidad&#44; mientras que 317 corresponden al macroestado de no uni&#243;n &#40;<a class="elsevierStyleCrossRef" href="#t0010">Tabla II</a>&#41;&#46; Las proporciones S&#47;k de los p&#233;ptidos asociados al macroestado de uni&#243;n oscilaron entre 7&#44;31 y 10&#44;49 para MSA-2&#44; y entre 7&#44;27 y 10&#44;49 para AMA-1 &#40;<a class="elsevierStyleCrossRefs" href="#t0005">Tablas I y II</a>&#41;&#46;</p><p id="p0155" class="elsevierStylePara elsevierViewall">De los 492 p&#233;ptidos analizados en cada una de las prote&#237;nas te&#243;ricas&#44; se encontr&#243; que 102&#44; 104 y 101 corresponden respectivamente al macroestado de uni&#243;n de cada una&#44; mientras que las restantes 390&#44; 391 y 388 corresponden al macroestado de no uni&#243;n &#40;ver <a class="elsevierStyleCrossRefs" href="#t0015">Anexos 1&#44; 2 y 3</a>&#41;&#46; El porcentaje de uni&#243;n respecto a la totalidad de p&#233;ptidos corresponde al 20&#46;73&#37; para la secuencia te&#243;rica 1&#44; al 21&#46;13&#37; para la 2 y al 20&#46;52&#37; para la 3&#46;</p><elsevierMultimedia ident="t0015"></elsevierMultimedia><elsevierMultimedia ident="t0020"></elsevierMultimedia><elsevierMultimedia ident="t0025"></elsevierMultimedia></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">DISCUSI&#211;N</span><p id="p0160" class="elsevierStylePara elsevierViewall">Este es el primer trabajo donde se realiza una predicci&#243;n de p&#233;ptidos non&#225;meros de MSA-2 y AMA-1 que pueden unirse al HLA clase II con base en una teor&#237;a basada en las leyes de probabilidad&#44; combinatoria y entrop&#237;a&#44; determinando que existen 35 p&#233;ptidos incluidos dentro del macroestado de uni&#243;n para MSA-2&#44; y 60 para AMA-1 como posibles ant&#237;genos &#250;tiles para el desarrollo de vacunas&#46; Adicionalmente se predijeron p&#233;ptidos de uni&#243;n en tres prote&#237;nas te&#243;ricas&#44; encontrando 102&#44; 104 y 101 p&#233;ptidos de uni&#243;n respectivamente&#44; evidenciando f&#237;sica y matem&#225;ticamente que el fen&#243;meno de uni&#243;n es caracterizado por una alta especificidad &#250;til en su predicci&#243;n&#46; Las prote&#237;nas te&#243;ricas fueron construidas sin ning&#250;n par&#225;metro de ordenamiento&#44; pues el algoritmo equiprobable cumple con las condiciones de ser un generador de n&#250;meros pseudo aleatorios&#44; sin embargo se encontr&#243; un orden constante de la proporci&#243;n de p&#233;ptidos predichos respecto a la totalidad posible cercano al 20&#37;&#44; evidenciando un orden subyacente a este fen&#243;meno aparentemente aleatorio&#46;</p><p id="p0165" class="elsevierStylePara elsevierViewall">Trabajos anteriores en predicci&#243;n de uni&#243;n de p&#233;ptidos han utilizado Redes neuronales artificiales&#44; ANN por sus siglas en ingles&#44; programaci&#243;n lineal&#44; vectores de m&#225;quina&#44; entre otros&#44; con el objetivo de cuantificar la uni&#243;n de p&#233;ptidos al HLA<a class="elsevierStyleCrossRefs" href="#bb0175"><span class="elsevierStyleSup">&#40;35-38&#41;</span></a>&#46; Uno de los trabajos m&#225;s recientes desarrollados&#44; disponible en internet y de amplia cobertura al&#233;lica es el NetMHCIIPAN<a class="elsevierStyleCrossRef" href="#bb0195"><span class="elsevierStyleSup">&#40;39&#41;</span></a>&#44; basado en redes neuronales&#59; su entrenamiento integra datos de todos los alelos&#44; regi&#243;n central de p&#233;ptidos&#44; composici&#243;n y tama&#241;o de los residuos de flanqueamiento de los terminales N y C&#44; tama&#241;o del p&#233;ptido recurso&#44; as&#237; como la afinidad normalizada de uni&#243;n&#46; Este m&#233;todo supone que la integraci&#243;n de todos estos datos en una red neuronal permite la predicci&#243;n del fen&#243;meno de uni&#243;n al HLA clase II&#44; sin embargo sus par&#225;metros dependen de la muestra de entrenamiento&#44; por lo que los resultados est&#225;n condicionados a la misma y a la muestra usada para probarlo&#44; haciendo limitada su generalizaci&#243;n&#46; A diferencia de estos planteamientos&#44; este trabajo se basa en una metodolog&#237;a de car&#225;cter general que parte de una inducci&#243;n f&#237;sica con 7 p&#233;ptidos non&#225;meros&#44; donde se desarrolla una metodolog&#237;a que no requiere entrenamientos y adem&#225;s no depende de la muestra de estudio para desarrollarse&#44; pues est&#225; basada en un experimento mental en el contexto de leyes f&#237;sicas y matem&#225;ticas permitiendo cuantificar la totalidad de posibilidades existentes de p&#233;ptidos<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">&#40;26&#41;</span></a>&#46;</p><p id="p0170" class="elsevierStylePara elsevierViewall">El oncogen HER-2&#47;neu es reconocido por producir una respuesta efectiva como ant&#237;geno tumoral&#44; especialmente en c&#225;ncer de mama y de ovario&#44; por lo cual se considera un buen candidato para desarrollar vacunas<a class="elsevierStyleCrossRef" href="#bb0200"><span class="elsevierStyleSup">&#40;40&#41;</span></a>&#44; mientras que el API m1 constituye un tratamiento adecuado para los pacientes que sufren de graves reacciones a picaduras de abeja<a class="elsevierStyleCrossRef" href="#bb0205"><span class="elsevierStyleSup">&#40;41&#41;</span></a>&#46; Siete secuencias del HER-2&#47;neu estudiadas experimentalmente &#40;HER62&#44; HER605&#44; HER648&#44; HER765&#44; HER822&#44; HER883&#44; HER1124&#41;&#44; as&#237; como la totalidad de p&#233;ptidos non&#225;meros del API m1 fueron evaluados con la teor&#237;a utilizada en el presente trabajo&#44; comprobando los resultados con los hallazgos experimentales de estas prote&#237;nas y se compar&#243; el desempe&#241;o con los resultados de los m&#233;todos de predicci&#243;n de p&#233;ptidos disponibles en l&#237;nea de mayor cobertura al&#233;lica&#44; obteniendo los mayores valores para la sensibilidad&#44; valor predictivo positivo y exactitud&#46;</p><p id="p0175" class="elsevierStylePara elsevierViewall">La teor&#237;a planteada deja a un lado los costosos procesos experimentales de ensayo y error&#44; por predicciones fisicas y matem&#225;ticas logrando una simplificaci&#243;n en la escogencia de los p&#233;ptidos&#46; En este caso&#44; en lugar de realizar un an&#225;lisis de la totalidad de las secuencias de las prote&#237;nas&#44; los esfuerzos del trabajo de laboratorio se dirigir&#237;an al 11&#46;67&#37; de los p&#233;ptidos en el caso de la prote&#237;na de MSA-2 y al 15&#46;92&#37; en la prote&#237;na AMA-1&#44; pues son las que presentan las caracter&#237;sticas matem&#225;ticas necesarias para unirse la HLA II seg&#250;n la teor&#237;a aqu&#237; planteada&#46;</p><p id="p0180" class="elsevierStylePara elsevierViewall">Como en las teor&#237;as fundamentales actuales de la f&#237;sica<a class="elsevierStyleCrossRefs" href="#bb0170"><span class="elsevierStyleSup">&#40;34&#44;42&#44;43&#41;</span></a> no hay causas sino &#243;rdenes f&#237;sicos y matem&#225;ticos acausales para la descripci&#243;n y comprensi&#243;n del fen&#243;meno estudiado&#46; Por ser una teor&#237;a no requiere de an&#225;lisis estad&#237;sticos ni del uso de grandes cantidades de datos experimentales&#46; Desde esta perspectiva f&#237;sica acausal han sido desarrolladas investigaciones en diversos campos de la medicina con resultados de aplicaci&#243;n experimental y cl&#237;nica&#46; Por ejemplo&#44; la teor&#237;a de conjuntos ha sido utilizada para el desarrollo de una caracterizaci&#243;n del fen&#243;meno de uni&#243;n de la prote&#237;na MSP-1 al receptor de gl&#243;bulo rojo<a class="elsevierStyleCrossRef" href="#bb0220"><span class="elsevierStyleSup">&#40;44&#41;</span></a>&#44; as&#237; como a la uni&#243;n de p&#233;ptidos nonam&#233;ricos al HLA clase II<a class="elsevierStyleCrossRef" href="#bb0225"><span class="elsevierStyleSup">&#40;45&#41;</span></a>&#46; Del mismo modo&#44; con base en las teor&#237;as de probabilidad y entrop&#237;a se caracteriz&#243; la uni&#243;n entre el receptor del eritrocito y los p&#233;ptidos de la proteina MSP-1<a class="elsevierStyleCrossRef" href="#bb0230"><span class="elsevierStyleSup">&#40;46&#41;</span></a>&#46; Siguiendo este camino&#44; la teor&#237;a desarrollada<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">&#40;26&#41;</span></a> logra simplificar este fen&#243;meno tan complejo&#44; mediante una generalizaci&#243;n que obvia la especificidad al&#233;lica&#44; caracterizando el fen&#243;meno de uni&#243;n a partir de representaciones num&#233;ricas de tipos de secuencias y no de amino&#225;cidos espec&#237;ficos&#46; Al transformar la informaci&#243;n experimental en informaci&#243;n num&#233;rica en el contexto de leyes de la f&#237;sica este trabajo evidencia un orden f&#237;sico y matem&#225;tico subyacente al fen&#243;meno de uni&#243;n entre el p&#233;ptido y el HLA clase II&#44; desde una perspectiva acausal que permite realizar predicciones &#250;tiles para el desarrollo de vacunas&#46;</p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">DECLARACI&#211;N DE CONFLICTO DE INTER&#201;S</span><p id="p0185" class="elsevierStylePara elsevierViewall">Los autores declaran no tener conflictos de inter&#233;s&#46;</p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">DEDICACI&#211;N</span><p id="p0190" class="elsevierStylePara elsevierViewall">A nuestros hijos&#46;</p></span></span>"
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          "titulo" => "DEDICACI&#211;N"
        ]
        11 => array:2 [
          "identificador" => "xack43907"
          "titulo" => "AGRADECIMIENTOS"
        ]
        12 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2009-07-24"
    "fechaAceptado" => "2009-09-24"
    "PalabrasClave" => array:2 [
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec151244"
          "palabras" => array:7 [
            0 => "Uni&#243;n"
            1 => "Probabilidad"
            2 => "Entrop&#237;a"
            3 => "Eritrocito"
            4 => "MSA-2"
            5 => "AMA-1"
            6 => "Simulaci&#243;n"
          ]
        ]
      ]
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Key words"
          "identificador" => "xpalclavsec151245"
          "palabras" => array:7 [
            0 => "Binding"
            1 => "Probability"
            2 => "Entropy"
            3 => "Erythrocyte"
            4 => "MSA-2"
            5 => "AMA-1"
            6 => "Simulation"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">El prop&#243;sito de esta investigaci&#243;n es aplicar la teor&#237;a de predicci&#243;n de uni&#243;n de p&#233;ptidos a la regi&#243;n central del HLA clase II&#44; a los p&#233;ptidos non&#225;meros de MSA-2&#44; y la prote&#237;na AMA-1 del <span class="elsevierStyleItalic">Plasmodium falciparum</span>&#44; y a los 492 p&#233;ptidos non&#225;meros sobrelapados de tres prote&#237;nas te&#243;ricas&#44; de 500 amino&#225;cidos cada una&#46;</p><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Se aplic&#243; una teor&#237;a predictiva de uni&#243;n al HLA clase II basada en la proporci&#243;n S&#47;k para la predicci&#243;n del fen&#243;meno de uni&#243;n de p&#233;ptidos de las prote&#237;nas MSA-2 y AMA-1 a la totalidad de secuencias de 20 amino&#225;cidos de dichas prote&#237;nas&#46; Se calcularon los valores de probabilidad&#44; combinatoria y entrop&#237;a de 300 secuencias non&#225;meras sobrelapadas de la prote&#237;na MSA- 2 y 372 de AMA-1&#46; Finalmente se construyeron tres prote&#237;nas te&#243;ricas de 500 amino&#225;cidos cada una a partir de una simulaci&#243;n computacional y se aplic&#243; la teor&#237;a para cuantificar la uni&#243;n de todos los p&#233;ptidos non&#225;meros sobrelapados de las mismas&#46;</p><p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Se predijo que 35 secuencias de MSA-2 y 60 de AMA-1 est&#225;n asociadas al macroestado de uni&#243;n mientras que 265 de MSA-2 y 317 de AMA-1 est&#225;n asociadas al macroestado de no uni&#243;n&#46; Se predijo que 102&#44; 104 y 101 secuencias de las tres prote&#237;nas construidas est&#225;n asociadas al macroestado de uni&#243;n&#44; mientras que las restantes 390&#44; 388 y 391 se asocian al macroestado de no uni&#243;n respectivamente&#46;</p><p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">La predicci&#243;n te&#243;rica desarrollada puede facilitar la escogencia de p&#233;ptidos implicados en el desarrollo de vacunas&#44; evidenciando que existe un orden f&#237;sico y matem&#225;tico subyacente a la presentaci&#243;n antig&#233;nica&#46;</p>"
      ]
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">The aim of this research is apply the predictive nonameric binding methodology to HLA class II central region&#44; to nonameric peptides of MSA-2 and AMA-1 proteins from <span class="elsevierStyleItalic">Plasmodium falciparum</span>&#44; and to 492 nonameric overlapped peptides for three theoretical proteins with size of 500 residues&#46;</p><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">A predictive binding theory to HLA class II based on S&#47;k proportion was applied in order to predict binding peptides of MSA-2 and AMA-1 proteins to all sequences with 20 residues size from these proteins&#46; The probability&#44; combinatory and entropy values were calculated for 300 nonameric overlapped sequences of MSA-2 and 372 of AMA-1&#46; Finally three theoretical proteins of 500 residues each one were made&#44; starting from a computational simulation and the theory was applied&#44; quantifying binding for all nonameric overlapped peptides for these proteins&#46;</p><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">35 sequences for MSA-2 and 60 for AMA-1 associated to binding macrostate while 265 for MSA-2 and 317 for AMA-1 associated to non binding macrostate were predicted&#46; 102&#44; 104 and 101 sequences associated to binding macrostate for the theoretical proteins while the others 390&#44; 388&#44; and 391 associated to non binding macrostate respectively were predicted&#46;</p><p id="sp0050" class="elsevierStyleSimplePara elsevierViewall">The theoretical prediction developed can facilitate the selection of peptides implied in vaccine development&#44; showing that mathematical and physical order lies to antigenic presentation&#46;</p>"
      ]
    ]
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#44;98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GTGGSGSAGSGAGASAGNGA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GAGASAGNGANPGADAERSP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NPGADAERSPSPTAPPATPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ERSPSPTAP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#44;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SPTAPPATPATTTTTTTTND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TTTTTTTTNDAEASTSTSSE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AEASTSTSSENPNHKNAETN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ASTSTSSEN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">8&#44;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">SSENPNHKN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">8&#44;27&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">NPNHKNAETNPKGKGEVQKP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">PKGKGEVQKPNQANKETQNN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">VQKPNQANK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">9&#44;1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">ENKGTGQHGHMHGSRNNHPQ&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">MHGSRNNHPQNTSDSQKECT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SRNNHPQNT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NTSDSQKECTDGNKENCGAA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab259170.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "es" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">P&#233;ptidos de uni&#243;n de la proteina MSA-2&#44; junto con sus valores de la proporci&#243;n S&#47;k para los pasos finales</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "t0010"
        "etiqueta" => "Tabla II"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
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                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab259171.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "es" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">P&#233;ptidos de uni&#243;n de la proteina AMA-1&#44; junto con sus valores de la proporci&#243;n S&#47;k para los pasos finales</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "t0015"
        "etiqueta" => "Anexo I"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
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                  \t\t\t\t">28-148&#46; WEDPMMNSY&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">58-280&#46; WDGVMMCDT&nbsp;\t\t\t\t\t\t\n
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                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab259173.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "es" => "<p id="sp0055" class="elsevierStyleSimplePara elsevierViewall">Secuencia te&#243;rica n&#250;mero 1 y p&#233;ptidos non&#225;meros de uni&#243;n de acuerdo con la predicci&#243;n&#46; Los n&#250;meros a la derecha de la numeraci&#243;n del p&#233;ptido indican el lugar del p&#233;ptido dentro de la secuencia&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "t0020"
        "etiqueta" => "Anexo II"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
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                  \t\t\t\t">7-28&#46; RRDWFPVKW&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">33-164&#46; MPRRADWDT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">59-302&#46; MIVTEWMLC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">42-226&#46; MRVHNWCRN&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">68-331&#46; LHMPLWNRN&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">94-453&#46; WHMGIPHLY&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">104-485&#46; MMFHFGYDA&nbsp;\t\t\t\t\t\t\n
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                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab259174.png"
              ]
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          ]
        ]
        "descripcion" => array:1 [
          "es" => "<p id="sp0060" class="elsevierStyleSimplePara elsevierViewall">Secuencia te&#243;rica n&#250;mero 2 y p&#233;ptidos non&#225;meros de uni&#243;n de acuerdo con la predicci&#243;n&#46; Los n&#250;meros a la derecha de la numeraci&#243;n del p&#233;ptido indican el lugar del p&#233;ptido dentro de la secuencia&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "t0025"
        "etiqueta" => "Anexo III"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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