Althaus Ernst, Kohlbacher Oliver, Lenhof Hans-Peter, Müller Peter
Max-Planck-Institut für Informatik, Stuhlsatzenhausweg 85, 66123 Saarbrücken, Germany.
J Comput Biol. 2002;9(4):597-612. doi: 10.1089/106652702760277336.
Rigid-body docking approaches are not sufficient to predict the structure of a protein complex from the unbound (native) structures of the two proteins. Accounting for side chain flexibility is an important step towards fully flexible protein docking. This work describes an approach that allows conformational flexibility for the side chains while keeping the protein backbone rigid. Starting from candidates created by a rigid-docking algorithm, we demangle the side chains of the docking site, thus creating reasonable approximations of the true complex structure. These structures are ranked with respect to the binding free energy. We present two new techniques for side chain demangling. Both approaches are based on a discrete representation of the side chain conformational space by the use of a rotamer library. This leads to a combinatorial optimization problem. For the solution of this problem, we propose a fast heuristic approach and an exact, albeit slower, method that uses branch-and-cut techniques. As a test set, we use the unbound structures of three proteases and the corresponding protein inhibitors. For each of the examples, the highest-ranking conformation produced was a good approximation of the true complex structure.
刚体对接方法不足以从两种蛋白质的未结合（天然）结构预测蛋白质复合物的结构。考虑侧链灵活性是迈向完全灵活的蛋白质对接的重要一步。这项工作描述了一种方法，该方法允许侧链具有构象灵活性，同时保持蛋白质主链刚性。从刚性对接算法创建的候选结构开始，我们解开对接位点的侧链，从而创建真实复合物结构的合理近似。这些结构根据结合自由能进行排序。我们提出了两种新的侧链解缠技术。两种方法都基于通过使用旋转异构体库对侧链构象空间进行离散表示。这导致了一个组合优化问题。为了解决这个问题，我们提出了一种快速启发式方法和一种精确但较慢的方法，该方法使用分支切割技术。作为测试集，我们使用三种蛋白酶和相应蛋白质抑制剂的未结合结构。对于每个例子，产生的排名最高的构象都是真实复合物结构的良好近似。
