Lin Ming, Chen Rong, Liang Jie
Department of Information & Decision Science, University of Illinois at Chicago, 845 S. Morgan St., Chicago, Illinois 60607, USA.
J Chem Phys. 2008 Feb 28;128(8):084903. doi: 10.1063/1.2831905.
Proteins contain many voids, which are unfilled spaces enclosed in the interior. A few of them have shapes compatible to ligands and substrates and are important for protein functions. An important general question is how the need for maintaining functional voids is influenced by, and affects other aspects of proteins structures and properties (e.g., protein folding stability, kinetic accessibility, and evolution selection pressure). In this paper, we examine in detail the effects of maintaining voids of different shapes and sizes using two-dimensional lattice models. We study the propensity for conformations to form a void of specific shape, which is related to the entropic cost of void maintenance. We also study the location that voids of a specific shape and size tend to form, and the influence of compactness on the formation of such voids. As enumeration is infeasible for long chain polymer, a key development in this work is the design of a novel sequential Monte Carlo strategy for generating large number of sample conformations under very constraining restrictions. Our method is validated by comparing results obtained from sampling and from enumeration for short polymer chains. We succeeded in accurate estimation of entropic cost of void maintenance, with and without an increasing number of restrictive conditions, such as loops forming the wall of void with fixed length, with additionally fixed starting position in the sequence. Additionally, we have identified the key structural properties of voids that are important in determining the entropic cost of void formation. We have further developed a parametric model to predict quantitatively void entropy. Our model is highly effective, and these results indicate that voids representing functional sites can be used as an improved model for studying the evolution of protein functions and how protein function relates to protein stability.
蛋白质含有许多空隙，这些空隙是内部封闭的未填充空间。其中一些空隙的形状与配体和底物相适配，对蛋白质功能很重要。一个重要的普遍问题是，维持功能性空隙的需求如何受到蛋白质结构和性质的其他方面（例如蛋白质折叠稳定性、动力学可达性和进化选择压力）的影响，以及它如何影响这些方面。在本文中，我们使用二维晶格模型详细研究了维持不同形状和大小空隙的影响。我们研究了构象形成特定形状空隙的倾向，这与维持空隙的熵成本有关。我们还研究了特定形状和大小的空隙倾向于形成的位置，以及紧凑性对这种空隙形成的影响。由于对长链聚合物进行枚举是不可行的，这项工作的一个关键进展是设计了一种新颖的序贯蒙特卡罗策略，用于在非常严格的限制条件下生成大量样本构象。我们的方法通过比较短聚合物链的采样结果和枚举结果进行了验证。我们成功地准确估计了维持空隙的熵成本，无论是否有越来越多的限制条件，例如形成具有固定长度的空隙壁的环，以及在序列中额外固定的起始位置。此外，我们已经确定了空隙的关键结构特性，这些特性在确定空隙形成的熵成本方面很重要。我们进一步开发了一个参数模型来定量预测空隙熵。我们的模型非常有效，这些结果表明，代表功能位点的空隙可以用作研究蛋白质功能进化以及蛋白质功能与蛋白质稳定性如何相关的改进模型。
