离子通道运输的原子到连续尺度计算方法

Voltage-gated K+ ion channels (Kv channels) are fundamentally important cellular machinery present in all animal cells and key components in the generation and propagation of electrical impulses in the nervous system. The accurate computer simulation of ion transport through Kv channels would be a major advance in biomedical research, allowing for the efficient design of novel drugs for a wide variety of pharmaceutical applications. However, the time scales necessary to study channel gating (~ms-s) is much longer than what can currently be reached via conventional atomistic simulations. Thus, new advanced algorithmic developments in multi-scale simulation techniques are urgently needed to study ion transport phenomena in biological systems..We propose here a novel multi-scaling technique based on algorithms recently successfully developed by us. Our approach goes significantly beyond earlier multi-scaling algorithms which usually involve a reduced representation of the biological system via use of coarse-graining techniques. In our technique, the channel is retained in its fully atomistic representation in both the fast (implicit) and detailed (explicit) modes, allowing for a fast and simple switching without loss of precision. This accuracy is the key to the success of capturing long-scale events of ion channel gating. The multi-scale model involves two stages: A slow mode with a fully atomistic representation of the ion channel and its environment. In the fast mode, implicit solvent models such as the hybrid electrostatic model using a reaction field, and the generalized Born implicit membrane model, will be used. These models, in which the solvent is represented as a polarizable continuum, allow for 30-100 times increase in the sampling speed of the ion channel dynamics, key for reaching ~ms timescales. The final level will use the PNP model of ion transport, with the MD simulation used to dynamically update the diffusion and dielectric constant in the PNP equations. PNP will allow to directly compare the simulations results with experimental conductance measurements for these class of ion channels and provide the benchmark for the entire project. .Our proposed multi-scale algorithm - based on proven simulation techniques developed by us – will provide a novel way to overcome the severe time-scale problem in simulating ion channels and will be widely applicable to numerous other systems of fundamental biological importance, such as transporters, pumps and signaling proteins.

电压门控钾离子(Kv)通道是动物细胞内极其重要的装置，例如是神经系统中电脉冲产生和传播的重要部件。Kv通道的研究,特别是高精度模拟有助于高效的新药设计。由于通道开闭的时间尺度(毫秒至秒)远超传统的原子模拟可达到的时间,多尺度模拟算法的建立与应用是非常急迫的问题。本项目将基于负责人过去的成果提出新型有效的多尺度算法。Kv通道模型包含二个时间尺度：慢模式使用全原子表示离子通道,膜和溶剂。在快模式中，将使用反应场混合模型和广义Born隐膜模型，膜和溶剂描述为极化的连续介质.这种混合方法可以将采样效率提高30~100倍，是达到毫秒时间尺度的关键所在。体系中的离子通道在隐式和显式模式下将保持全原子表示，在保持精度下在两个模式间快速和简单的转换。在宏观层次使用离子输运的PNP模型，并利用分子动力学模拟更新PNP中的扩散系数和介电常数。PNP将可以直接比较离子通道电导率的实测数据，为本项目提供基准数据。

这个项目基金主要用在开发先进方法研究离子通道和膜蛋白问题。在这些问题上，我们已经取得了一些重大突破，比如，在模拟中首次直接观察到钠离子通道中离子过膜现象，同样在幽门螺旋杆菌的UreI型通道研究中也直接观察到尿素分子过膜。.此外，我们通过直接模拟多肽分布过程提出了SecY易位子在界面相互作用下的一种可能工作机制。 使用这些方法，我们同时也研究了抗菌肽在生物膜膜中如何自发形成通道的过程。在隐式水静电作用模型模拟方法中，我们也做了一些工作。.目前我们还在进行许多后续研究，包括钠离子通道和UreI型尿素通道中药物分子与靶点如何结合及相互作用的模拟研究。

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