Georgiev Ivelin, Lilien Ryan H, Donald Bruce R
Dartmouth Computer Science Department, Hanover, NH 03755, USA.
Bioinformatics. 2006 Jul 15;22(14):e174-83. doi: 10.1093/bioinformatics/btl220.
Structure-based protein redesign can help engineer proteins with desired novel function. Improving computational efficiency while still maintaining the accuracy of the design predictions has been a major goal for protein design algorithms. The combinatorial nature of protein design results both from allowing residue mutations and from the incorporation of protein side-chain flexibility. Under the assumption that a single conformation can model protein folding and binding, the goal of many algorithms is the identification of the Global Minimum Energy Conformation (GMEC). A dominant theorem for the identification of the GMEC is Dead-End Elimination (DEE). DEE-based algorithms have proven capable of eliminating the majority of candidate conformations, while guaranteeing that only rotamers not belonging to the GMEC are pruned. However, when the protein design process incorporates rotameric energy minimization, DEE is no longer provably-accurate. Hence, with energy minimization, the minimized-DEE (MinDEE) criterion must be used instead.
In this paper, we present provably-accurate improvements to both the DEE and MinDEE criteria. We show that our novel enhancements result in a speedup of up to a factor of more than 1000 when applied in redesign for three different proteins: Gramicidin Synthetase A, plastocyanin, and protein G.
Contact authors for source code.
基于结构的蛋白质重新设计有助于构建具有所需新功能的蛋白质。在保持设计预测准确性的同时提高计算效率一直是蛋白质设计算法的主要目标。蛋白质设计的组合性质既源于允许残基突变，也源于蛋白质侧链柔性的纳入。在单个构象可以模拟蛋白质折叠和结合的假设下，许多算法的目标是识别全局最小能量构象（GMEC）。识别GMEC的一个主导定理是死端消除（DEE）。基于DEE的算法已被证明能够消除大多数候选构象，同时保证仅修剪不属于GMEC的旋转异构体。然而，当蛋白质设计过程纳入旋转异构体能量最小化时，DEE不再能保证准确。因此，在进行能量最小化时，必须使用最小化DEE（MinDEE）标准。
在本文中，我们提出了对DEE和MinDEE标准的可证明准确的改进。我们表明，当应用于三种不同蛋白质（短杆菌肽合成酶A、质体蓝素和蛋白G）的重新设计时，我们的新颖改进可使速度提高多达1000倍。
如需源代码，请联系作者。
