Huang Qiang, Korte Thomas, Rachakonda P Sivaramakrishna, Knapp Ernst-Walter, Herrmann Andreas
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
Proteins. 2009 Feb 1;74(2):291-303. doi: 10.1002/prot.22157.
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 coiled-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.
流感病毒与宿主细胞内体膜的融合由同源三聚体组织的糖蛋白血凝素（HA）介导。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亚基经历从环到螺旋的转变，形成卷曲螺旋结构，这是许多介导融合的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与HA2从环到螺旋的转变之间没有直接关系。为了解释这一观察结果，我们使用基于介电连续介质溶剂模型的计算方法来探索水和pH对转变自由能变化的影响。计算结果表明，HA2片段与水之间的静电相互作用是导致卷曲螺旋结构的HA2从环到螺旋转变的主要驱动力，只要覆盖处于非融合活性构象的HA2亚基的HA1球状结构域发生重组，从而使水分子能够与HA2亚基的整个环段相互作用。此外，我们表明，从环到螺旋转变释放的能量可能占驱动膜融合后续步骤所需的能量。这种水驱动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。
