Virtual states introduced for overcoming entropic barriers in conformational space
Virtual states introduced for overcoming entropic barriers in conformational space
复制标题
引入虚拟态来克服构象空间中的熵障碍
DOI：
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Haruki Nakamura
中科院分区：
文献类型：
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作者：
J. Higo;Haruki Nakamura
自由能景观是研究生物分子系统大规模运动的一个重要量值，因为它描绘了运动的可能路径。当地貌由热力学稳定状态(低能盆地)组成时，这些状态通过狭窄的构象路径(即瓶颈)相连，这种狭窄减缓了构象采样中的盆地间往返。这导致了盆地自由能的不准确。即使沿着反应坐标相当好地执行增强的构象采样，这一困难也不会被消除。在这项研究中，为了加强跨流域往返，我们引入了一个覆盖狭窄通道的虚拟状态。基于状态间转移(真实状态盆地和虚拟状态之间的转移)的详细平衡条件来控制虚拟状态的概率分布函数。为了模拟真实生物系统的自由能景观，我们引入了一个简单的模型，其中一堵墙将两个盆地隔开，并在墙上钻一个狭窄的洞来连接两个盆地。采用蒙特卡罗(MC)方法进行抽样。我们考察了几种空穴大小和态间转移概率。对于较小的空穴尺寸，较小的态间跃迁几率产生的采样效率是传统MC的100倍。这一结果与人们的直觉相反，因为人们通常认为抽样效率随着转移概率的增加而增加。本方法适用于增强构象采样，如多正则或自适应伞形采样，并可扩展到分子动力学。
Free-energy landscape is an important quantity to study large-scale motions of a biomolecular system because it maps possible pathways for the motions. When the landscape consists of thermodynamically stable states (low-energy basins), which are connected by narrow conformational pathways (i.e., bottlenecks), the narrowness slows the inter-basin round trips in conformational sampling. This results in inaccuracy of free energies for the basins. This difficulty is not cleared out even when an enhanced conformational sampling is fairly performed along a reaction coordinate. In this study, to enhance the inter-basin round trips we introduced a virtual state that covers the narrow pathways. The probability distribution function for the virtual state was controlled based on detailed balance condition for the inter-state transitions (transitions between the real-state basins and the virtual state). To mimic the free-energy landscape of a real biological system, we introduced a simple model where a wall separates two basins and a narrow hole is pierced in the wall to connect the basins. The sampling was done based on Monte Carlo (MC). We examined several hole-sizes and inter-state transition probabilities. For a small hole-size, a small inter-state transition probability produced a sampling efficiency 100 times higher than a conventional MC does. This result goes against ones intuition, because one considers generally that the sampling efficiency increases with increasing the transition probability. The present method is readily applicable to enhanced conformational sampling such as multi-canonical or adaptive umbrella sampling, and extendable to molecular dynamics.