Solvent dramatically affects protein structure refinement
Solvent dramatically affects protein structure refinement
复制标题
DOI：
10.1073/pnas.0810818105
复制
发表时间：
2008-12-23
影响因子：
11.1
通讯作者：
Levitt, Michael
中科院分区：
文献类型：
--
作者：
Chopra, Gaurav;Summa, Christopher M.;Levitt, Michael
蛋白质结构预测中最具挑战性的问题之一是改进同源模型（天然结构的1-3埃C-α rmsd内的结构），也称为蛋白质结构精化问题。它已被证明，可以实现改进，使用在真空中的能量最小化与分子力学和统计推导的连续可微的混合知识为基础的（KB）的潜在功能。然而，球状蛋白质在体内和体外的水溶液中折叠并发挥功能。在这项工作中，我们研究了溶剂在蛋白质结构精修中的作用。在显式溶剂中的分子动力学和显式和隐式溶剂中的能量最小化进行了一组75个天然蛋白质，以测试各种能量势。对每种天然蛋白质的729个近天然诱饵进行了更严格的细化测试。我们使用了一个强大的收敛能量最小化方法，以显示隐式溶剂（GBSA）提供了更大的改善一些蛋白质比KB潜力：24的75个蛋白质显示出平均改善> 20%的C-α rmsd从天然结构与GBSA相比，只有7个蛋白质与KB。在明确的溶剂中的分子动力学移动的结构进一步远离其天然构象比初始的，未精制的诱饵。隐式溶剂产生一个深而光滑的势能吸引子盆地，将其拉向原生结构。
One of the most challenging problems in protein structure prediction is improvement of homology models (structures within 1-3 angstrom C-alpha rmsd of the native structure), also known as the protein structure refinement problem. It has been shown that improvement could be achieved using in vacuo energy minimization with molecular mechanics and statistically derived continuously differentiable hybrid knowledge-based (KB) potential functions. Globular proteins, however, fold and function in aqueous solution in vivo and in vitro. In this work, we study the role of solvent in protein structure refinement. Molecular dynamics in explicit solvent and energy minimization in both explicit and implicit solvent were performed on a set of 75 native proteins to test the various energy potentials. A more stringent test for refinement was performed on 729 near-native decoys for each native protein. We use a powerfully convergent energy minimization method to show that implicit solvent (GBSA) provides greater improvement for some proteins than the KB potential: 24 of 75 proteins showing an average improvement of > 20% in C-alpha rmsd from the native structure with GBSA, compared to just 7 proteins with KB. Molecular dynamics in explicit solvent moved the structures further away from their native conformation than the initial, unrefined decoys. Implicit solvent gives rise to a deep, smooth potential energy attractor basin that pulls toward the native structure.