Leach A R
Department of Chemistry, University of Southampton, U.K.
J Mol Biol. 1994 Jan 7;235(1):345-56. doi: 10.1016/s0022-2836(05)80038-5.
An algorithm is described that explores the conformational degrees of freedom of the amino acid side-chains and of the ligand when docking a putative ligand into a receptor site. For a given orientation of the ligand relative to the protein, the method can find the lowest energy combination of amino acid side-chains and ligand conformations as well as all other combinations in order of increasing energy within a specified energy cutoff. The amino acid side-chains and the ligand are restricted to discrete low-energy conformations, determined for the former by analysing high-resolution protein structures and in the latter case from a conformational analysis. Coupled to an algorithm for exploring the six degrees of orientational freedom of the ligand with respect to the receptor, the method can be used to perform conformationally flexible ligand docking. A combination of two search methods is employed to explore the conformational degrees of freedom: Dead End Elimination and the A* algorithm. When no ligand is present the approach can be used to predict the lowest energy combinations of side-chain conformations for a given protein backbone structure. The approach is employed to illustrate how such a procedure can be used to estimate the conformational entropy change that accompanies the formation of an intermolecular complex between a protein and a ligand and to demonstrate that the protein's conformational entropy may in some cases increase on binding the ligand. This is due to a modification of the protein's energy hypersurface that makes more conformational states accessible. Our results highlight the need for appropriate methods to estimate the strength of binding.
本文描述了一种算法，该算法在将假定配体对接至受体位点时，探索氨基酸侧链和配体的构象自由度。对于配体相对于蛋白质的给定取向，该方法能够找到氨基酸侧链和配体构象的最低能量组合，以及在指定能量截止范围内按能量递增顺序排列的所有其他组合。氨基酸侧链和配体被限制在离散的低能量构象中，前者通过分析高分辨率蛋白质结构确定，后者则通过构象分析确定。与用于探索配体相对于受体的六个取向自由度的算法相结合，该方法可用于进行构象灵活的配体对接。采用两种搜索方法的组合来探索构象自由度：死端消除法和A*算法。当不存在配体时，该方法可用于预测给定蛋白质主链结构的侧链构象的最低能量组合。该方法用于说明如何使用这样的程序来估计蛋白质与配体之间形成分子间复合物时伴随的构象熵变化，并证明在某些情况下，蛋白质结合配体时其构象熵可能会增加。这是由于蛋白质能量超曲面的改变，使得更多的构象状态可及。我们的结果强调了需要适当的方法来估计结合强度。
