Characterizing a Histidine Switch Controlling pH-Dependent Conformational Changes of the Influenza Virus Hemagglutinin
Characterizing a Histidine Switch Controlling pH-Dependent Conformational Changes of the Influenza Virus Hemagglutinin
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DOI：
10.1016/j.bpj.2013.06.047
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发表时间：
2013-08-20
影响因子：
3.4
通讯作者：
Tajkhorshid, Emad
中科院分区：
文献类型：
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作者：
Kalani, Mohamad R.;Moradi, Abdulvahab;Tajkhorshid, Emad
在流感病毒与宿主细胞融合过程中，血凝素的HA2链以ph依赖的方式弯曲成发夹状结构，促进了病毒包膜与内体膜的融合。为了表征HA2的铰链区域对pH变化的结构和动力学响应，并检查该区域中一个保守的组氨酸（铰链组氨酸）的作用，我们在中性和低pH条件下，通过铰链组氨酸的质子化状态的变化，对包含几种血凝素亚型铰链区域的26个残基肽进行了广泛的分子动力学（MD）模拟。为了研究组氨酸质子化对铰链区结构动力学的影响，在隐式和显式溶剂中进行了70多组MD模拟（总计25.1 μ s）。在显式和隐式溶剂模拟中，在所有模拟中，组氨酸的质子化都一致地观察到铰链弯曲，从初始的直螺旋构象开始，而具有中性组氨酸的系统在整个模拟过程中保持其主要的直构象。相反，MD模拟从最初的弯曲构象开始，在铰链组氨酸中和后形成了直螺旋结构，而当铰链组氨酸保持质子化时，弯曲结构保持不变。最后，铰链组氨酸到丙氨酸的突变完全消除了肽的弯曲反应。一种基于铰链组氨酸与邻近酸性残基相互作用的分子机制被提出用于控制铰链构象。我们提出，当组氨酸作为pH传感器时，这可能是pH控制螺旋结构变化的共同机制。
During the fusion of the influenza virus to the host cell, bending of the HA2 chain of hemagglutinin into a hairpin-shaped structure in a pH-dependent manner facilitates the fusion of the viral envelope and the endosomal membrane. To characterize the structural and dynamical responses of the hinge region of HA2 to pH changes and examine the role of a conserved histidine in this region (the hinge histidine), we have performed an extensive set of molecular dynamics (MD) simulations of 26-residue peptides encompassing the hinge regions of several hemagglutinin subtypes under both neutral and low pH conditions, modeled by the change of the protonation state of the hinge histidine. More than 70 sets of MD simulations (collectively amounting to 25.1 mu s) were performed in both implicit and explicit solvents to study the effect of histidine protonation on structural dynamics of the hinge region. In both explicit and implicit solvent simulations, hinge bending was consistently observed upon the protonation of the histidine in all the simulations starting with an initial straight helical conformation, whereas the systems with a neutral histidine retained their primarily straight conformation throughout the simulations. Conversely, the MD simulations starting from an initially bent conformation resulted in the formation of a straight helical structure upon the neutralization of the hinge histidine, whereas the bent structure was maintained when the hinge histidine remained protonated. Finally, mutation of the hinge histidine to alanine abolishes the bending response of the peptide altogether. A molecular mechanism based on the interaction of the hinge histidine with neighboring acidic residues is proposed to be responsible for its role in controlling the conformation of the hinge. We propose that this might present a common mechanism for pH-controlled structural changes in helical structures when histidines act as the pH sensor.