Termodinámica de la unión de Ca2+ a hemicanales de hCx2
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Archivos
Fecha
2023
Autores
Profesor/a Guía
Facultad/escuela
Idioma
es
Título de la revista
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Editor
Universidad Andrés Bello
Nombre de Curso
Licencia CC
Licencia CC
Resumen
Los canales de unión en hendidura (GJC por sus siglas en inglés: Gap Junction Channel) son
canales presentes en eucariontes, formados por dos hemicanales (HCs) o conexones que
conectan los citoplasmas de dos células adyacentes. Cada HC se compone de seis proteínas
llamadas conexinas (Cx) y pueden estar desacoplados, conectando el citoplasma con el
espacio extracelular. Los HC que no forman GJC participan de varios procesos fisiológicos y
suelen estar cerrados en condiciones fisiológicas, aunque su apertura puede ser gatillada por
cambios en las concentraciones extracelulares de Ca
2+
. No obstante, luego de años de
estudios, aún no hay consenso en la comunidad dedicada al tema, sobre el mecanismo
mediante el cual los iones calcio regulan la apertura y cierre de los HC, particularmente de HC
formados por Cx26, una de las conexinas más estudiadas. La aplicación de protocolos de
simulación molecular como complemento a los estudios experimentales han ayudado a estudiar
las relaciones estructura-función de estos canales. En este trabajo se realizaron protocolos de
modelamiento comparativo de proteínas y simulación molecular para generar las diversas
combinaciones posibles de HC-Cx26 unida a calcio, considerando sus 6 monómeros. Con los
diferentes modelos planteados y aplicación de la técnica conocida como transformación
alquímica, se estudió el efecto termodinámico asociado a la unión de iones calcio. Los
resultados indican que no hay una preferencia termodinámica entre las diferentes
configuraciones de las mismas cantidades de ion calcio en el sistema, además, indican que el
proceso de unión de iones Ca
2+ no presenta propiedades cooperativas en cuanto a la
termodinámica asociada y que el sacar iones calcio del sistema es desfavorable
energéticamente.
Gap Junction Channels (GJC) are channels found in eukaryotes, formed by two hemichannels (HCs) or connexons that connect the cytoplasms of two adjacent cells. Each HC is composed of six proteins called connexins (Cx) and may be uncoupled, connecting the cytoplasm with the extracellular space. HCs that do not form GJC participate in various physiological processes and are typically closed under physiological conditions, although their opening can be triggered by changes in extracellular Ca2+ concentrations. However, after years of studies, there is still no consensus in the community dedicated to the subject regarding the mechanism by which calcium ions regulate the opening and closing of HCs, particularly HCs formed by Cx26, one of the most studied connexins. The application of molecular simulation protocols as a complement to experimental studies has helped explore the structure-function relationships of these channels. In this investigation, comparative protein modeling protocols and molecular simulation were conducted to generate various possible combinations of Ca2+-bound Cx26 HC, considering its 6 monomers. With different models and the application of the alchemical transformation technique, the thermodynamic effect associated with the binding of calcium ions was studied. The results indicate that there is no thermodynamic preference among different configurations with the same amounts of calcium ion in the system. Additionally, they suggest that the Ca2+ binding process does not exhibit cooperative properties in terms of associated thermodynamics and the unbinding of calcium ions is unfavorable energetically.
Gap Junction Channels (GJC) are channels found in eukaryotes, formed by two hemichannels (HCs) or connexons that connect the cytoplasms of two adjacent cells. Each HC is composed of six proteins called connexins (Cx) and may be uncoupled, connecting the cytoplasm with the extracellular space. HCs that do not form GJC participate in various physiological processes and are typically closed under physiological conditions, although their opening can be triggered by changes in extracellular Ca2+ concentrations. However, after years of studies, there is still no consensus in the community dedicated to the subject regarding the mechanism by which calcium ions regulate the opening and closing of HCs, particularly HCs formed by Cx26, one of the most studied connexins. The application of molecular simulation protocols as a complement to experimental studies has helped explore the structure-function relationships of these channels. In this investigation, comparative protein modeling protocols and molecular simulation were conducted to generate various possible combinations of Ca2+-bound Cx26 HC, considering its 6 monomers. With different models and the application of the alchemical transformation technique, the thermodynamic effect associated with the binding of calcium ions was studied. The results indicate that there is no thermodynamic preference among different configurations with the same amounts of calcium ion in the system. Additionally, they suggest that the Ca2+ binding process does not exhibit cooperative properties in terms of associated thermodynamics and the unbinding of calcium ions is unfavorable energetically.
Notas
Memoria (Ingeniero en Biotecnología)
Palabras clave
Canales de Calcio, Hemicanales