Computational simulations of asymmetric fluxes of large molecules through gap junction channel pores. (7th January 2017)

• Record Type: Journal Article
• Authors: Mondal, Abhijit; Appadurai, Daniel A.; Akoum, Nazem W.; Sachse, Frank B.; Moreno, Alonso P.
• Is Part Of: Journal of theoretical biology. Volume 412(2017)
• Page Start: 61
• Page End: 73
• Publication Date: 2017-01-07
• Subjects: Gap junctions -- Connexins -- Heterotypic -- Asymmetric flux -- Computational model -- Brownian dynamics simulation; Biology -- Periodicals; Biological Science Disciplines -- Periodicals; Biology -- Periodicals; Biologie -- Périodiques; Theoretische biologie; Biology; Periodicals; 571.05
• DOI: 10.1016/j.jtbi.2016.08.040
• Languages: English
• ISSNs: 0022-5193

Abstract

Abstract: Gap junction channels are formed out of connexin isoforms, which enable molecule and ion selective diffusion amongst neighboring cells. HeLa cells expressing distinct connexins (Cx) allow the formation of heterotypic channels, where we observed a molecular charge-independent preferential flux of large fluorescent molecules in the Cx45 to Cx43 direction. We hypothesize that the pore's shape is a significant factor along-side charge and transjunctional voltages for this asymmetric flux. To test this hypothesis, we developed a 3D computational model simulating Brownian diffusion of large molecules in a gap junction channel pore. The basic pore contour was derived from x-ray crystallographic structures of Cx43 and Cx26 and approximated using basic geometric shapes. Lucifer yellow dye molecules and cesium counter-ions were modeled as spheres using their respective Stokes radii. Our simulation results from simple diffusion and constant concentration gradient experiments showed that only charged particles yield asymmetric fluxes in heterotypic pores. While increasing the inner mouth size resulted in a near-quadratic rise in flux, the rise was asymptotic for outer mouth radii increase. Probability maps and average force per particle per pore section explain the asymmetric flux with variation in pore shape. Furthermore, the simulation results are in agreement with our in vitro experimental results with HeLa cells in Cx43-Cx45 heterotypic configurations. The presence of asymmetric fluxes can help us to understand effects of the molecular structure of the pore and predict potential differences in vivo . Graphical abstract: Highlights: A 3D computational model of a gap junction pore with Brownian particle dynamics has been developed. Particle fluxes have been studied in simple diffusion and forced concentration gradient conditions. The impact of pore shape on flux has been demonstrated using our computational model. Simulations and in vitro experiments indicate the importance of particle charge and transjunctional voltage for asymmetric fluxes in heterotypic gap junction pores.