Ligand-Induced Conformational and Dynamical Changes in a GT-B Glycosyltransferase: Molecular Dynamics Simulations of Heptosyltransferase I Complexes.
Ligand-Induced Conformational and Dynamical Changes in a GT-B Glycosyltransferase: Molecular Dynamics Simulations of Heptosyltransferase I Complexes.
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DOI：
10.1021/acs.jcim.1c00868
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发表时间：
2022-01-24
影响因子：
5.6
通讯作者：
Taylor EA
中科院分区：
文献类型：
--
作者：
Hassan BA;Milicaj J;Ramirez-Mondragon CA;Sham YY;Taylor EA
了解庚糖基转移酶I（HepI）的动力学运动和配体识别基序对于识别其他糖基转移酶（GT）的行为至关重要。我们实验室先前的研究已经证明，GT-B结构类中的GT，其特征在于它们通过接头区域连接两个Rossman样结构域，具有保守的结构折叠和动力学运动，尽管序列同源性低，因此使HepI中发现的发现可转移到其他GT-B酶。通过分子动力学模拟和配体结合自由能分析的HepI在载脂蛋白和绑定复合物（所有动力学相关的组合的天然底物/产品），我们已经确定了积极有利的酶途径配体结合和释放。我们的主成分，动态互相关，和网络分析的模拟揭示了相关的运动，涉及的N-末端结构域内的残基与C-末端结构域残基通过近端氨基酸残基和功能基团的结合基板。分析的结构变化，能量的底物/产物结合，和pKa的变化已经阐明了各种内部和内部的相互作用，是关键的酶催化。这些数据证实了我们的实验观察到的蛋白质构象变化中观察到的两个presteady状态动力学和圆二色性分析的HepI。这些模拟提供了宝贵的结构的见解，在配体结合后，在HepI构象重排所涉及的区域。了解特定的相互作用，管理构象变化可能会加强我们的努力，开发新的动力学破坏抑制剂对GT-B结构酶在未来。
Understanding the dynamical motions and ligand recognition motifs of heptosyltransferase I (HepI) can be critical to discerning the behavior of other glycosyltransferase (GT) enzymes. Prior studies in our lab have demonstrated that GTs in the GT-B structural class, which are characterized by their connection of two Rossman-like domains by a linker region, have conserved structural fold and dynamical motions, despite low sequence homology, therefore making discoveries found in HepI transferable to other GT-B enzymes. Through molecular dynamics simulations and ligand binding free energy analysis of HepI in the apo and bound complexes (for all kinetically relevant combinations of the native substrates/products), we have determined the energetically favored enzymatic pathway for ligand binding and release. Our principal component, dynamic cross correlation, and network analyses of the simulations have revealed correlated motions involving residues within the N-terminal domain communicating with C-terminal domain residues via both proximal amino acid residues and also functional groups of the bound substrates. Analyses of the structural changes, energetics of substrate/product binding, and changes in pKa have elucidated a variety of inter and intradomain interactions that are critical for enzyme catalysis. These data corroborate our experimental observations of protein conformational changes observed in both presteady state kinetic and circular dichroism analyses of HepI. These simulations provided invaluable structural insights into the regions involved in HepI conformational rearrangement upon ligand binding. Understanding the specific interactions governing conformational changes is likely to enhance our efforts to develop novel dynamics disrupting inhibitors against GT-B structural enzymes in the future.
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