Brownian Dynamics Simulations including Explicit Atoms for Modeling Transport through Nanopores

布朗动力学模拟，包括用于模拟纳米孔传输的显式原子

• 批准号: 452270316
• 负责人: Professor Dr. Ulrich Kleinekathöfer
• 金额: --
• 依托单位: Department of Physics and Earth Sciences
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/452270316?language=en
• 关键词: Brownian; Dynamics; Simulations; including; Explicit

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.

在自然科学和医学的许多领域中，通过纳米孔的运输是至关重要的。例如，革兰氏阴性细菌具有一层外膜，作为渗透这些细菌的物理屏障。通过膜孔的易位通常是抗生素进入这些细胞的唯一途径。只有对有限数量的膜孔和抗菌化合物，流入细菌是相当好的理解。目前，抗生素易位的原子模拟对于单个孔隙和化合物的组合是可行的，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-孔隙组合是不可行的。另一个孔的例子是炭疽毒素的通道形成保护性抗原（PA63）成分，由于其纯粹的大小，在全原子水平上的传输模拟在数值上是昂贵的。该项目侧重于布朗动力学方法，包括称为BRODEA的显式原子。该方案的第一个版本最近已经开发出来，并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力场表示结合起来。布朗动力学框架中可能包含的显式原子允许放松刚性通道，特别是刚性衬底假设。本项目的目的之一是改进布朗动力学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隙的组合，其中分子动力学数据存在或将被计算。BRODEA方法将用于多种抗生素分子通过病原菌的一系列孔蛋白的易位，这些孔蛋白的结构最近才被解决。对于带电分子，可以使用电场控制，而对于中性化合物，需要确定自由能面。附加的计算将涉及二价离子对这些易位过程的影响。这些对各种化合物和通道的计算将给出一个评估，在这种情况下，新的混合方法可以被用来产生可靠的结果。此外，BRODEA方法可以促进一种快速而合理可靠的方法来模拟毒素的长通道。由于离子通过炭疽毒素的通道形成保护性抗原（PA63）组分的运输尚未在分子动力学水平上进行研究，因此我们预计这样的模拟将为随后的混合布朗分子动力学计算获得一些基准数据。此后，可能阻断通道的分子将被研究。