Centre for Integrative Bioinformatics VU (IBIVU), VU University Amsterdam, Amsterdam, The Netherlands.
Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
Biophys J. 2011 Feb 2;100(3):693-700. doi: 10.1016/j.bpj.2010.11.088.
The folding specificity of proteins can be simulated using simplified structural models and knowledge-based pair-potentials. However, when the same models are used to simulate systems that contain many proteins, large aggregates tend to form. In other words, these models cannot account for the fact that folded, globular proteins are soluble. Here we show that knowledge-based pair-potentials, which include explicitly calculated energy terms between the solvent and each amino acid, enable the simulation of proteins that are much less aggregation-prone in the folded state. Our analysis clarifies why including a solvent term improves the foldability. The aggregation for potentials without water is due to the unrealistically attractive interactions between polar residues, causing artificial clustering. When a water-based potential is used instead, polar residues prefer to interact with water; this leads to designed protein surfaces rich in polar residues and well-defined hydrophobic cores, as observed in real protein structures. We developed a simple knowledge-based method to calculate interactions between the solvent and amino acids. The method provides a starting point for modeling the folding and aggregation of soluble proteins. Analysis of our simple model suggests that inclusion of these solvent terms may also improve off-lattice potentials for protein simulation, design, and structure prediction.
蛋白质的折叠特异性可以使用简化的结构模型和基于知识的对势能来模拟。然而，当相同的模型用于模拟包含许多蛋白质的系统时，往往会形成大的聚集体。换句话说，这些模型无法解释折叠的球状蛋白质是可溶的这一事实。在这里，我们表明，包括溶剂与每个氨基酸之间的显式计算能量项的基于知识的对势能，可以模拟在折叠状态下聚合倾向较小的蛋白质。我们的分析阐明了为什么包括溶剂项可以提高折叠能力。没有水的势能的聚合是由于极性残基之间不切实际的吸引力相互作用，导致人为聚类。相反，当使用基于水的势能时，极性残基更倾向于与水相互作用；这导致设计的蛋白质表面富含极性残基和明确定义的疏水性核心，如在真实蛋白质结构中观察到的那样。我们开发了一种简单的基于知识的方法来计算溶剂和氨基酸之间的相互作用。该方法为可溶性蛋白质的折叠和聚集建模提供了一个起点。对我们简单模型的分析表明，包含这些溶剂项也可能改善蛋白质模拟、设计和结构预测的非晶格势能。
