Brownian Dynamics Simulations including Explicit Atoms for Modeling Transport through Nanopores

通过纳米孔的传输在自然科学和医学的许多领域中都具有关键的重要性。例如，革兰氏阴性细菌拥有一层外膜，作为渗透到这些细菌的物理屏障。透过膜孔的移位通常是将抗生素带入这些细胞的唯一途径。只有对于有限数量的膜孔和抗菌化合物，才能合理地很好地理解流入细菌的情况。如今，抗生素易位的原子模拟对于毛孔和化合物的单独组合是可行的，但在数值上相当昂贵。因此，分子动力学模拟对于测试大量的分子-孔组合是不可行的。另一个孔隙的例子是炭疽毒素的通道形成保护性抗原(PA63)成分。由于炭疽毒素的大小，在全原子水平上的运输模拟在数值上是昂贵的。该项目的重点是布朗动力学方法，包括被称为BRODEA的显式原子。这个方案的第一个版本是最近开发的，它试图将布朗动力学模拟的计算效率与系统重要部分的完全原子化的力场表示相结合。显性原子可能包含在布朗动力学框架中，这允许放松刚性通道，特别是刚性底物假设。本项目的一个目标是改进布朗框架和分子动力学框架之间的静电描述。此外，该方法将进一步验证分子和孔的组合，其中分子动力学数据已经存在或将被计算。BRODEA方法将被用于各种抗生素分子通过一系列最近才被解析的致病菌孔道的移位。对于带电分子可以使用电场引导，而对于中性化合物，需要确定自由能面。额外的计算将涉及二价离子对这些移位过程的影响。这些对各种化合物和通道的计算将给出评估，在这种情况下，可以使用新的混合方法来产生可靠的结果。此外，BRODEA方法可以促进一种快速而合理可靠的方式来对长时间的毒素通道进行模拟。由于炭疽毒素的通道形成保护性抗原(PA63)组分的离子传输还没有在分子动力学水平上进行研究，我们预计这样的模拟将为后续的混合布朗分子动力学计算提供一些基准数据。此后，将对可能阻止该通道的分子进行调查。

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.