Kolinski A, Rotkiewicz P, Ilkowski B, Skolnick J
Laboratory of Computational Genomics and Bioinformatics, Danforth Plant Science Center, CET, St. Louis, Missouri 63108, USA.
Proteins. 1999 Dec 1;37(4):592-610. doi: 10.1002/(sici)1097-0134(19991201)37:4<592::aid-prot10>3.0.co;2-2.
A new method for the homology-based modeling of protein three-dimensional structures is proposed and evaluated. The alignment of a query sequence to a structural template produced by threading algorithms usually produces low-resolution molecular models. The proposed method attempts to improve these models. In the first stage, a high-coordination lattice approximation of the query protein fold is built by suitable tracking of the incomplete alignment of the structural template and connection of the alignment gaps. These initial lattice folds are very similar to the structures resulting from standard molecular modeling protocols. Then, a Monte Carlo simulated annealing procedure is used to refine the initial structure. The process is controlled by the model's internal force field and a set of loosely defined restraints that keep the lattice chain in the vicinity of the template conformation. The internal force field consists of several knowledge-based statistical potentials that are enhanced by a proper analysis of multiple sequence alignments. The template restraints are implemented such that the model chain can slide along the template structure or even ignore a substantial fraction of the initial alignment. The resulting lattice models are, in most cases, closer (sometimes much closer) to the target structure than the initial threading-based models. All atom models could easily be built from the lattice chains. The method is illustrated on 12 examples of target/template pairs whose initial threading alignments are of varying quality. Possible applications of the proposed method for use in protein function annotation are briefly discussed.
提出并评估了一种基于同源性的蛋白质三维结构建模新方法。将查询序列与穿线算法生成的结构模板进行比对，通常会产生低分辨率的分子模型。所提出的方法试图改进这些模型。在第一阶段，通过对结构模板的不完全比对进行适当追踪并连接比对间隙，构建查询蛋白折叠的高配位晶格近似。这些初始晶格折叠与标准分子建模协议产生的结构非常相似。然后，使用蒙特卡罗模拟退火程序来优化初始结构。该过程由模型的内力场和一组宽松定义的约束条件控制，这些约束条件使晶格链保持在模板构象附近。内力场由几个基于知识的统计势组成，通过对多序列比对的适当分析得到增强。模板约束的实现方式使得模型链可以沿着模板结构滑动，甚至可以忽略很大一部分初始比对。在大多数情况下，得到的晶格模型比基于初始穿线的模型更接近（有时是更接近得多）目标结构。所有原子模型都可以很容易地从晶格链构建。该方法在12个目标/模板对的例子上进行了说明，其初始穿线比对质量各不相同。简要讨论了所提出的方法在蛋白质功能注释中的可能应用。
