Mendes J, Baptista A M, Carrondo M A, Soares C M
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.
Proteins. 1999 Dec 1;37(4):530-43. doi: 10.1002/(sici)1097-0134(19991201)37:4<530::aid-prot4>3.0.co;2-h.
Side-chain modeling has a widespread application in many current methods for protein tertiary structure determination, prediction, and design. Of the existing side-chain modeling methods, rotamer-based methods are the fastest and most efficient. Classically, a rotamer is conceived as a single, rigid conformation of an amino acid sidechain. Here, we present a flexible rotamer model in which a rotamer is a continuous ensemble of conformations that cluster around the classic rigid rotamer. We have developed a thermodynamically based method for calculating effective energies for the flexible rotamer. These energies have a one-to-one correspondence with the potential energies of the rigid rotamer. Therefore, the flexible rotamer model is completely general and may be used with any rotamer-based method in substitution of the rigid rotamer model. We have compared the performance of the flexible and rigid rotamer models with one side-chain modeling method in particular (the self-consistent mean field theory method) on a set of 20 high quality crystallographic protein structures. For the flexible rotamer model, we obtained average predictions of 85.8% for chi1, 76.5% for chi1+2 and 1.34 A for root-mean-square deviation (RMSD); the corresponding values for core residues were 93.0%, 87.7% and 0.70 A, respectively. These values represent improvements of 7.3% for chi1, 8.1% for chi1+2 and 0.23 A for RMSD over the predictions obtained with the rigid rotamer model under otherwise identical conditions; the corresponding improvements for core residues were 6.9%, 10.5% and 0.43 A, respectively. We found that the predictions obtained with the flexible rotamer model were also significantly better than those obtained for the same set of proteins with another state-of-the-art side-chain placement method in the literature, especially for core residues. The flexible rotamer model represents a considerable improvement over the classic rigid rotamer model. It can, therefore, be used with considerable advantage in all rotamer-based methods commonly applied to protein tertiary structure determination, prediction, and design and also in predictions of free energies in mutational studies.
侧链建模在当前许多用于蛋白质三级结构测定、预测和设计的方法中有着广泛应用。在现有的侧链建模方法中，基于旋转异构体的方法是最快且最有效的。传统上，一个旋转异构体被视为氨基酸侧链的单一刚性构象。在此，我们提出一种灵活的旋转异构体模型，其中一个旋转异构体是围绕经典刚性旋转异构体聚集的连续构象集合。我们开发了一种基于热力学的方法来计算灵活旋转异构体的有效能量。这些能量与刚性旋转异构体的势能一一对应。因此，灵活旋转异构体模型具有完全的通用性，可用于任何基于旋转异构体的方法中以替代刚性旋转异构体模型。我们在一组20个高质量晶体学蛋白质结构上，将灵活和刚性旋转异构体模型与一种特定的侧链建模方法（自洽平均场理论方法）的性能进行了比较。对于灵活旋转异构体模型，我们得到的χ1平均预测值为85.8%，χ1 + 2平均预测值为76.5%，均方根偏差（RMSD）为1.34 Å；核心残基的相应值分别为93.0%、87.7%和0.70 Å。这些值相较于在其他相同条件下使用刚性旋转异构体模型得到的预测值，χ1提高了7.3%，χ1 + 2提高了8.1%，RMSD减小了0.23 Å；核心残基的相应提高分别为6.9%、10.5%和0.43 Å。我们发现，使用灵活旋转异构体模型得到的预测结果也明显优于文献中另一种用于同一组蛋白质的最新侧链放置方法得到的预测结果，尤其是对于核心残基。灵活旋转异构体模型相较于经典刚性旋转异构体模型有显著改进。因此，它可在通常应用于蛋白质三级结构测定、预测和设计的所有基于旋转异构体的方法中具有相当大的优势，也可用于突变研究中的自由能预测。
