Zhu Yuzhen, Yang Shuang, Qi Ruxi, Zou Yu, Ma Buyong, Nussinov Ruth, Zhang Qingwen
College of Physical Education and Training, Shanghai University of Sport , 399 Chang Hai Road, Shanghai 200438, China.
Department of Physics, Fudan University , 220 Handan Road, Shanghai 200433, China.
J Phys Chem B. 2015 Nov 5;119(44):14236-44. doi: 10.1021/acs.jpcb.5b07962. Epub 2015 Oct 16.
Neuronal calcium sensor-1 (NCS-1) protein has been implicated in multiple neuronal functions by binding partners mostly through a largely exposed hydrophobic crevice (HC). In the absence of a ligand, the C-terminal tail (loop L3, residues D176 to V190) binds directly to the HC pocket as a ligand mimetic, occupying the HC and regulating its conformational stability. A recent experimental study reported that L3 deletion resulted in global structure destabilization. However, the influence of C-terminal tail on the conformations of NCS-1 protein is unclear at the atomic level. In this study, we investigated the structural properties and the conformational dynamics of wild type NCS-1 and L3 truncation variant by extensive all-atom molecular dynamics (MD) simulations. Our cumulative 2 μs MD simulations demonstrated that L3 deletion increased the structural flexibility of the C-domain and the distant N-domain. The community network analysis illustrated that C-terminal tail truncation weakened the interdomain correlation. Moreover, our data showed that the variant significantly disrupted the salt bridges network and expanded simultaneously the global structure and HC. These conformational changes caused by C-terminal tail truncation may affect the regulation of target interactions. Our study provides atomic details of the conformational dynamics effects of the C-terminal tail on human wild type NCS-1.
神经元钙传感器-1（NCS-1）蛋白主要通过一个大部分暴露的疏水裂缝（HC）与结合伙伴相互作用，从而参与多种神经元功能。在没有配体的情况下，C末端尾巴（环L3，残基D176至V190）作为配体模拟物直接结合到HC口袋中，占据HC并调节其构象稳定性。最近的一项实验研究报告称，L3缺失导致整体结构不稳定。然而，C末端尾巴对NCS-1蛋白构象的影响在原子水平上尚不清楚。在本研究中，我们通过广泛的全原子分子动力学（MD）模拟研究了野生型NCS-1和L3截短变体的结构特性和构象动力学。我们累计2微秒的MD模拟表明，L3缺失增加了C结构域和远处N结构域的结构灵活性。群落网络分析表明，C末端尾巴截短削弱了结构域间的相关性。此外，我们的数据表明，该变体显著破坏了盐桥网络，同时扩大了整体结构和HC。由C末端尾巴截短引起的这些构象变化可能会影响对靶标相互作用的调节。我们的研究提供了C末端尾巴对人类野生型NCS-1构象动力学影响的原子细节。
