Energetics of the loop-to-helix transition leading to the coiled-coil structure of influenza virus hemagglutinin HA2 subunits
Energetics of the loop-to-helix transition leading to the coiled-coil structure of influenza virus hemagglutinin HA2 subunits
复制标题
导致流感病毒血凝素HA2亚基卷曲螺旋结构的环到螺旋转变的能量学
DOI：
10.1002/prot.22157
复制
发表时间：
2009-02-01
影响因子：
2.9
通讯作者：
Herrmann, Andreas
中科院分区：
文献类型：
--
作者：
Huang, Qiang;Korte, Thomas;Herrmann, Andreas
流感病毒与宿主细胞内体膜的融合是由同源三聚体组织的糖蛋白血凝素（HA）介导的。其融合活性由影响HA1和HA2亚基结构的低pH介导的构象变化触发。HA2亚基经历环到螺旋的转变，导致编码螺旋结构，这是许多融合介导病毒蛋白的高度保守基序。然而，实验研究表明，HA2卷曲螺旋结构在中性和低pH下是稳定的，这意味着低pH和HA2环到螺旋转变之间没有直接关系。为了解释这一观察结果，我们使用了基于介电连续溶剂模型的计算方法来探索水和pH值对过渡自由能变化的影响。计算结果表明，HA2片段和水之间的静电相互作用是HA2环到螺旋转变的主要驱动力，导致卷曲螺旋结构，只要覆盖HA2亚基的非融合能力构象的HA1球状结构域被重组，从而允许水分子与HA2亚基的整个环段相互作用。此外，我们表明，环到螺旋过渡释放的能量可能占驱动膜融合的后续步骤所需的能量。这种水驱动的过程可能类似于包膜病毒高度保守的卷曲螺旋基序形成的一般机制。
Fusion of influenza virus with the endosomal membrane of the host cell is mediated by the homotrimer-organized glycoprotein hemagglutinin (HA). Its fusion activity is triggered by a low pH-mediated conformational change affecting the structure of the HA1 and HA2 subunits. The HA2 subunits undergo a loop-to-helix transition leading to a coded-coil structure, a highly conserved motif for many fusion mediating viral proteins. However, experimental studies showed that the HA2 coiled-coil structure is stable at neutral and low pH, implying that there is no direct relationship between low pH and the HA2 loop-to-helix transition. To interpret this observation, we used a computational approach based on the dielectric continuum solvent model to explore the influence of water and pH on the free energy change of the transition. The computations showed that the electrostatic interaction between HA2 fragments and water is the major driving force of the HA2 loop-to-helix transition leading to the coiled-coil structure, as long as the HA1 globular domain covering the HA2 subunits in the nonfusion competent conformation is reorganized and thereby allows water molecules to interact with the whole loop segments of the HA2 subunits. Moreover, we show that the energy released by the loop-to-helix transition may account for those energies required for driving the subsequent steps of membrane fusion. Such a water-driven process may resemble a general mechanism for the formation of the highly conserved coiled-coil motif of enveloped viruses.