Computational Mapping of Anchoring Spots on Protein Surfaces
Computational Mapping of Anchoring Spots on Protein Surfaces
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DOI：
10.1016/j.jmb.2010.07.021
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发表时间：
2010-09-10
影响因子：
5.6
通讯作者：
Eisenstein, Miriam
中科院分区：
文献类型：
--
作者：
Ben-Shimon, Avraham;Eisenstein, Miriam
蛋白质蛋白质和蛋白质肽相互作用通常由涉及热点残基的少数强接触控制。这种接触的计算检测，这里称为锚定点，对于理解识别过程和预测相互作用是重要的;它是设计相互作用界面和治疗剂的重要步骤。我们描述ANCHORSMAP，蛋白质表面上的氨基酸侧链的计算映射的算法。该算法由两个阶段组成：一个基于几何的阶段（LSMdet），其中检测到足以结合单侧链的子口袋，并将氨基酸探针分散在它们附近，以及一个基于能量的阶段，其中通过重复的能量最小化和聚类附近的姿势来确定探针的最佳位置，并计算它们的Δ G。ANCHORSMAP采用了一种新的Delta G计算函数，该函数是专门为蛋白质-蛋白质识别而设计的，通过引入静电能量项的校正来补偿与探针结合的假设蛋白质所施加的介电屏蔽，该算法成功地检测了已知的锚定位点并准确地定位了探针。计算的Δ G在未结合蛋白质产生的图谱中的正确锚定点排名靠前。我们发现，Arg，Trp，Glu和Tyr，这是最喜欢的热点残基，也更有选择性的结合环境。锚定点映射的有用性通过检测蛋白质-蛋白质复合物bamase/barstar和蛋白质-肽复合物激酶/PKI中的结合表面，以及通过鉴定核转运蛋白NTF 2表面上的苯丙氨酸锚定位点、PDZ结构域上的C-末端锚定和嗜热菌蛋白酶上的苯酚锚定来证明。最后，我们讨论了锚点在分子识别过程中的作用。(C)2010爱思唯尔有限公司版权所有。
Protein protein and protein peptide interactions are often controlled by few strong contacts that involve hot spot residues. Computational detection of such contacts, termed here anchoring spots, is important for understanding recognition processes and for predicting interactions; it is an essential step in designing interaction interfaces and therapeutic agents. We describe ANCHORSMAP, an algorithm for computational mapping of amino acid side chains on protein surfaces. The algorithm consists of two stages: A geometry based stage (LSMdet), in which sub-pockets adequate for binding single side chains are detected and amino acid probes are scattered near them, and an energy based stage in which optimal positions of the probes are determined through repeated energy minimization and clustering of nearby poses and their Delta G are calculated. ANCHORSMAP employs a new function for Delta G calculations, which is specifically designed for the context of protein-protein recognition by introducing a correction in the electrostatic energy term that compensates for the dielectric shielding exerted by a hypothetical protein bound to the probe.The algorithm successfully detects known anchoring sites and accurately positions the probes. The calculated Delta G rank high the correct anchoring spots in maps produced for unbound proteins. We find that Arg, Trp, Glu and Tyr, which are favorite hot spot residues, are also more selective of their binding environment. The usefulness of anchoring spots mapping is demonstrated by detecting the binding surfaces in the protein-protein complex bamase/barstar and the protein-peptide complex kinase/PKI, and by identifying phenylalanine anchoring sites on the surface of the nuclear transporter NTF2, C-terminus anchors on PDZ domains and phenol anchors on thermolysin. Finally, we discuss the role of anchoring spots in molecular recognition processes. (C) 2010 Elsevier Ltd. All rights reserved.