Department of Physics, National Laboratory of Solid State Microstructure, Nanjing University, Nanjing, China.
Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China.
PLoS Comput Biol. 2022 Jun 2;18(6):e1010195. doi: 10.1371/journal.pcbi.1010195. eCollection 2022 Jun.
Allosteric communication between distant parts of proteins controls many cellular functions, in which metal ions are widely utilized as effectors to trigger the allosteric cascade. Due to the involvement of strong coordination interactions, the energy landscape dictating the metal ion binding is intrinsically rugged. How metal ions achieve fast binding by overcoming the landscape ruggedness and thereby efficiently mediate protein allostery is elusive. By performing molecular dynamics simulations for the Ca2+ binding mediated allostery of the calmodulin (CaM) domains, each containing two Ca2+ binding helix-loop-helix motifs (EF-hands), we revealed the key role of water-bridged interactions in Ca2+ binding and protein allostery. The bridging water molecules between Ca2+ and binding residue reduces the ruggedness of ligand exchange landscape by acting as a lubricant, facilitating the Ca2+ coupled protein allostery. Calcium-induced rotation of the helices in the EF-hands, with the hydrophobic core serving as the pivot, leads to exposure of hydrophobic sites for target binding. Intriguingly, despite being structurally similar, the response of the two symmetrically arranged EF-hands upon Ca2+ binding is asymmetric. Breakage of symmetry is needed for efficient allosteric communication between the EF-hands. The key roles that water molecules play in driving allosteric transitions are likely to be general in other metal ion mediated protein allostery.
蛋白质中远距离部分之间的变构通讯控制着许多细胞功能，其中金属离子被广泛用作效应子来触发变构级联。由于涉及到强配位相互作用，决定金属离子结合的能量景观本质上是崎岖不平的。金属离子如何通过克服景观崎岖来实现快速结合，从而有效地介导蛋白质变构，这仍然难以捉摸。通过对钙调蛋白（CaM）结构域的 Ca2+结合介导的变构作用进行分子动力学模拟，每个结构域包含两个 Ca2+结合螺旋-环-螺旋模体（EF 手），我们揭示了水桥相互作用在 Ca2+结合和蛋白质变构中的关键作用。Ca2+和结合残基之间的桥接水分子充当润滑剂，降低配体交换景观的崎岖度，从而促进 Ca2+偶联的蛋白质变构。EF 手螺旋的钙诱导旋转，以疏水性核心为枢轴，导致暴露用于靶标结合的疏水性位点。有趣的是，尽管结构相似，但两个对称排列的 EF 手在 Ca2+结合时的响应是不对称的。EF 手之间有效的变构通讯需要打破对称性。水分子在驱动变构转变中所起的关键作用可能在其他金属离子介导的蛋白质变构中具有普遍性。
