Stiebritz Martin T, Muller Yves A
Lehrstuhl für Biotechnik, Institut für Biologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestrasse 91, D-91052 Erlangen, Germany.
Acta Crystallogr D Biol Crystallogr. 2006 Jun;62(Pt 6):648-58. doi: 10.1107/S0907444906013333. Epub 2006 May 12.
In recent years, significant progress has been achieved in automation of the crystal structure-determination process. However, the final part of this process, namely the refinement of the atomic model, is still tedious for biological macromolecules because, especially at lower resolution, it requires extensive manual intervention. Here, it is shown that computer algorithms widely used in protein-design approaches can substantially simplify this process, helping to identify the correct orientation of the side chains during refinement. This approach was implemented into the computer program MUMBO. As in many protein-design programs, side-chain rotamer diversity is generated using rotamer libraries. The selection of the best combination of side-chain orientations is based on either the dead-end elimination (DEE) theorem or a Metropolis Monte Carlo approach and on a detailed atomic scoring function that describes the molecular interactions between the rotamers. We show that this scoring function can be easily extended and complemented through the introduction of an X-ray pseudo-energy calculated from the electron density present at the position of the rotamer. This extension is fully compatible with present protein-design algorithms and it is shown for a number of test cases that using this approach model refinement is simplified and convergence occurs faster.
近年来，晶体结构测定过程的自动化取得了显著进展。然而，该过程的最后一部分，即原子模型的精修，对于生物大分子来说仍然很繁琐，因为特别是在较低分辨率下，它需要大量的人工干预。在此，研究表明，蛋白质设计方法中广泛使用的计算机算法可以大大简化这一过程，有助于在精修过程中确定侧链的正确取向。这种方法被应用到计算机程序MUMBO中。与许多蛋白质设计程序一样，使用旋转异构体库生成侧链旋转异构体多样性。侧链取向最佳组合的选择基于死端消除（DEE）定理或 metropolis 蒙特卡罗方法，以及描述旋转异构体之间分子相互作用的详细原子评分函数。我们表明，通过引入根据旋转异构体位置处的电子密度计算出的X射线伪能量，可以轻松扩展和补充该评分函数。这种扩展与现有的蛋白质设计算法完全兼容，并且在多个测试案例中表明，使用这种方法可以简化模型精修并加快收敛速度。
