Isvoran A, Craescu C T, Alexov E
Department of Chemistry, West University of Timisoara, Pestallozi 16, 300115 Timisoara, Romania.
Eur Biophys J. 2007 Mar;36(3):225-37. doi: 10.1007/s00249-006-0123-1. Epub 2007 Feb 7.
The paper reports the results of numerical calculations of the pKa's of the ionizable groups and the electrostatic interactions between calmodulin lobes in three different states of calmodulin: calcium-free, peptide-free; calcium-loaded, peptide-free; and calcium-loaded, peptide-bound. NMR and X-ray studies revealed that in these states the overall structure of calmodulin adopts various conformations referred as: disordered semi-compact, extended and compact conformations, respectively. In addition, a new X-ray structure was recently reported (Structure, 2003, 11, 1303) showing that calcium-loaded, peptide-free calmodulin can also adopt a compact conformation in addition to the well known extended conformation. The calculated energy changes of calcium-loaded, peptide-free calmodulin along the pathway connecting these two conformations provide a possible explanation for this structural plasticity. The effect of pH and organic compounds in the solution phase on the preference of calmodulin to adopt compact or extended conformations may be thus rationalized. Analysis of the contribution of the ionization changes to the energy of association of calmodulin lobes suggested that the formation of the compact forms requires protonation of several acidic residues. However, two different protonation scenarios are revealed: a protonation due to internal lobe organization and thus independent of the lobes association, and a protonation induced by the lobes association resulting to a proton uptake. In addition, the role of the individual residues on the energy of association of calmodulin lobes is calculated in two compact conformations (peptide-free and peptide-bound) and is shown that a set of residues always plays a dominant role in inter-domain interactions.
本文报道了钙调蛋白三种不同状态下可电离基团的pKa值以及钙调蛋白叶之间静电相互作用的数值计算结果：无钙、无肽；有钙、无肽；有钙、有肽结合。核磁共振和X射线研究表明，在这些状态下，钙调蛋白的整体结构分别呈现出各种构象，即无序半紧密、伸展和紧密构象。此外，最近报道了一种新的X射线结构（《结构》，2003年，第11卷，第1303页），表明有钙、无肽的钙调蛋白除了众所周知的伸展构象外，也可以呈现紧密构象。计算出的有钙、无肽的钙调蛋白在连接这两种构象的途径上的能量变化为这种结构可塑性提供了一种可能的解释。因此，可以解释溶液相中pH值和有机化合物对钙调蛋白采用紧密或伸展构象偏好的影响。对电离变化对钙调蛋白叶结合能贡献的分析表明，紧密形式的形成需要几个酸性残基质子化。然而，揭示了两种不同的质子化情况：一种是由于叶内部组织导致的质子化，因此与叶的结合无关，另一种是由叶的结合诱导的质子化，导致质子摄取。此外，计算了两种紧密构象（无肽和有肽结合）中单个残基对钙调蛋白叶结合能的作用，结果表明一组残基在域间相互作用中总是起主导作用。
