Re-evaluation of low-resolution crystal structures via interactive molecular-dynamics flexible fitting (iMDFF): a case study in complement C4
Re-evaluation of low-resolution crystal structures via interactive molecular-dynamics flexible fitting (iMDFF): a case study in complement C4
复制标题
DOI：
10.1107/s2059798316012201
复制
发表时间：
2016-09-01
影响因子：
2.2
通讯作者：
Andersen, Gregers Rom
中科院分区：
文献类型：
--
作者：
Croll, Tristan Ian;Andersen, Gregers Rom
尽管蛋白质数据库中高分辨率结构的快速增长为启动模型提供了丰富的模板集，但过去和现在的许多结构至少部分是通过低分辨率和/或弱电子密度手工构建的。使用当前的模型构建工具，这项任务可能具有挑战性，并且基于dmax不超过3.5埃的数据的结构中可接受错误率（以原子碰撞和不利的主链和侧链构象的形式）的事实标准反映了这一点。当与模型偏差等其他因素结合在一起时，这些残余误差可能会导致蛋白质折叠中更严重的误差难以或不可能被检测到。最近发表的补体C4的3个3.6-4.2埃分辨率结构（PDB条目4fxg， 4fxk和4xam）在R-free和MolProbity评分方面均位于同等分辨率结构的前四分之一，然而，如图所示，在6个β链中包含寄存器错误。通过应用明确模拟原子间作用力的分子动力学力场，从而排除大多数物理上不可能的构象，最近开发的相互作用分子动力学柔性拟合（iMDFF）方法显着降低了人工重建过程中需要搜索的构象空间的复杂性。这大大提高了检测和校正寄存器错误的速度，并允许在分辨率低于3.5埃的地图中用户引导的模型构建收敛到具有与原子分辨率结构相当的立体化学质量的解决方案。在这里，iMDFF被用来单独纠正和重新完善这三种结构，使其MolProbity得分为
While the rapid proliferation of high-resolution structures in the Protein Data Bank provides a rich set of templates for starting models, it remains the case that a great many structures both past and present are built at least in part by hand-threading through low-resolution and/or weak electron density. With current model-building tools this task can be challenging, and the de facto standard for acceptable error rates (in the form of atomic clashes and unfavourable backbone and side-chain conformations) in structures based on data with dmax not exceeding 3.5 angstrom reflects this. When combined with other factors such as model bias, these residual errors can conspire to make more serious errors in the protein fold difficult or impossible to detect. The three recently published 3.6-4.2 angstrom resolution structures of complement C4 (PDB entries 4fxg, 4fxk and 4xam) rank in the top quartile of structures of comparable resolution both in terms of R-free and MolProbity score, yet, as shown here, contain register errors in six beta-strands. By applying a molecular-dynamics force field that explicitly models interatomic forces and hence excludes most physically impossible conformations, the recently developed interactive molecular-dynamics flexible fitting (iMDFF) approach significantly reduces the complexity of the conformational space to be searched during manual rebuilding. This substantially improves the rate of detection and correction of register errors, and allows user-guided model building in maps with a resolution lower than 3.5 angstrom to converge to solutions with a stereochemical quality comparable to atomic resolution structures. Here, iMDFF has been used to individually correct and re-refine these three structures to MolProbity scores of