Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1.
Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1.
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DOI：
10.1007/s10822-011-9484-3
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发表时间：
2011-11
影响因子：
3.5
通讯作者：
Cavasotto, Claudio N.
中科院分区：
文献类型：
--
作者：
Anisimov, Victor M.;Ziemys, Arturas;Kizhake, Smitha;Yuan, Ziyan;Natarajan, Amarnath;Cavasotto, Claudio N.
关键词：
BRCA1 (BRCT) 的 C 端结构域通过识别相互作用蛋白中的 pSXXF 基序参与 DNA 修复途径。据报道，含有该基序的短肽在微摩尔范围内与 BRCA1（BRCT）具有高特异性结合。在这项工作中，通过计算和实验研究了 pSXXF 肽的结合，以表征它们与 BRCA1 (BRCT) 的相互作用。阐明驱动蛋白质-配体相互作用的接触对于开发高亲和力小分子 BRCA1 抑制剂至关重要。分子动力学模拟揭示了肽 P+2 位置上的苏氨酸在为结合状态的配体提供结构刚性方面的关键作用。 P+1 处的突变影响较小。在 N 末端位置用萘基氨基酸延伸的肽表现出结合亲和力的适度增加，这可以通过萘基侧链与疏水性补丁的分散相互作用来解释。考虑了三种计算机终点方法来计算结合自由能。分子力学泊松-玻尔兹曼表面积 (MM/PB-SA) 和溶剂化相互作用能 (SIE) 与实验数据相当一致，Pearlman 预测指数分别为 0.71 和 0.78。 MM-量子力学-表面积 (MM-QMSA) 方法产生了改进的结果，其特征是 Pearlman 指数为 0.78。相关系数分别为0.59、0.61和0.69。在终点结合自由能方案中应用 QM 水平的理论的能力可能为持续提高计算机辅助药物设计的准确性提供一种方法。
The C-terminal domain of BRCA1 (BRCT) is involved in the DNA repair pathway by recognizing the pSXXF motif in interacting proteins. It has been reported that short peptides containing this motif bind to BRCA1(BRCT) in the micromolar range with high specificity. In this work, the binding of pSXXF peptides has been studied computationally and experimentally in order to characterize their interaction with BRCA1(BRCT). Elucidation of the contacts that drive the protein-ligand interactions is critical for the development of high affinity small-molecule BRCA1 inhibitors. Molecular dynamics simulations revealed the key role of threonine at the peptide P+2 position in providing structural rigidity to the ligand in the bound state. The mutation at P+1 had minor effects. Peptide extension at the N-terminal position with the naphthyl amino acid exhibited a modest increase in binding affinity, what could be explained by the dispersion interaction of the naphthyl side-chain with a hydrophobic patch. Three in silico end-point methods were considered for the calculation of binding free energy. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PB-SA) and the Solvated Interaction Energy (SIE) gave reasonable agreement with experimental data, exhibiting a Pearlman predictive index of 0.71 and 0.78, respectively. The MM-Quantum Mechanics-Surface Area (MM-QMSA) method yielded improved results, which was characterized by a Pearlman index of 0.78. The correlation coefficients were 0.59, 0.61 and 0.69, respectively. The ability to apply a QM level of theory within an end-point binding free energy protocol may provide a way for a consistent improvement of accuracy in computer-aided drug design.
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DOI：
10.1007/bf00548085
发表时间：
1977-01-01
期刊：
THEORETICA CHIMICA ACTA
影响因子：
--
作者：
DEWAR, MJS;THIEL, W
通讯作者：
THIEL, W
影响因子：
5.6
作者：
Cui, Qizhi;Sulea, Traian;O. Purisima, Enrico
通讯作者：
O. Purisima, Enrico
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
5.7
作者：
Campbell, Stephen J.;Edwards, Ross A.;Glover, J. N. Mark
通讯作者：
Glover, J. N. Mark