Brownian Dynamics Simulations including Explicit Atoms for Modeling Transport through Nanopores

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Transport through nanopores is of key importance in many fields of natural sciences and medicine. For example, Gram-negative bacteria possess an outer membrane which serves as a physical barrier for the penetration into these bacteria. The translocation of through membrane pores is often the only pathway to get antibiotics into these cells. Only for a limited number of membrane pores and antimicrobial compounds, the influx into the bacteria is reasonably well understood. Atomistic simulations of antibiotics translocations are these days feasible for individual combinations of pores and compounds but numerically quite expensive. Thus, molecular dynamics simulations are unfeasible for testing larger numbers of molecule-pore combinations. Another example of a pore, for which transport simulations at an all-atom level are numerically expensive just due the sheer size, is the channel-forming protective antigen (PA63) component of the anthrax toxin.The project focuses on a Brownian dynamics approach including explicit atoms termed BRODEA. A first version of this scheme has been developed recently and tries to combine the computational efficiency of Brownian dynamics simulations with a fully atomistic force field representation for important parts of the system. The possible inclusion of explicit atoms into the Brownian dynamics framework allows to relax the rigid channel and especially the rigid substrate assumption. One aim of the present project is to improve the electrostatic description between the Brownian and the molecular dynamics frameworks. Moreover, the approach will be further validated for combinations of molecules and pores for which either molecular dynamics data exist or will be calculated.The BRODEA approach will be employed to the translocation of a variety of antibiotics molecules through a series of porins of pathogenic bacteria for which the structures were only resolved recently. While for charged molecules steering by electric fields can be used, for neutral compounds, free energy surfaces need to be determined. Additional calculations will involve the effect of divalent ions on these translocation processes. These calculations for a variety of compounds and channels will give an assessment in which case the new hybrid approach can be employed to yield reliable results.Moreover, the BRODEA approach can facilitate a fast yet reasonably reliable way of performing simulations for long channels of toxins. Since the ion transport through the channel-forming protective antigen (PA63) component of the anthrax toxin has not yet been studied on the molecular dynamics level, we foresee such simulations to obtain some benchmark data for the subsequent mixed Brownian-molecular dynamics calculations. Thereafter, molecules potentially blocking the channel will be investigated.