Impact of calcium on N1 influenza neuraminidase dynamics and binding free energy.
Impact of calcium on N1 influenza neuraminidase dynamics and binding free energy.
复制标题
DOI：
10.1002/prot.22761
复制
发表时间：
2010-08-15
影响因子：
2.9
通讯作者：
McCammon, J. Andrew
中科院分区：
文献类型：
--
作者：
Lawrenz, Morgan;Wereszczynski, Jeff;Amaro, Rommie;Walker, Ross;Roitberg, Adrian;McCammon, J. Andrew
关键词：
高致病性流感病毒株H5 N1和H1N1目前用病毒表面蛋白神经氨酸酶（N1）的抑制剂治疗。N1的晶体结构表明位于活性位点附近的保守的高亲和力钙结合位点。这种钙在酶机制中的具体作用尚不清楚，尽管它已被证明对酶活性和热稳定性很重要。我们报告的分子动力学（MD）模拟的钙结合和无钙N1复合物与抑制剂奥司他韦（销售的药物达菲），独立使用AMBER FF 99 SB和GROMOS 96力场，给结构的关键框架残基的钙稳定。Y347在两个力场的模拟中表现出相似的采样模式，被认为是一个重要的N1残基，可以将配体“钳”成有利的结合姿势。自由能微扰和热力学积分计算，使用两种不同的力场，支持Y347的重要性，并表明在不存在钙的情况下，奥司他韦的结合自由能发生+3至+5 kcal/mol的变化。随着神经氨酸酶抑制剂的基于结构的药物设计的重要作用和越来越多的文献中出现的菌株和亚型，包括这种钙活性位点的稳定性是特别重要的计算工作，如同源建模，虚拟筛选，和自由能方法。Proteins 2010.© 2010 Wiley-Liss，Inc.
The highly pathogenic influenza strains H5N1 and H1N1 are currently treated with inhibitors of the viral surface protein neuraminidase (N1). Crystal structures of N1 indicate a conserved, high affinity calcium binding site located near the active site. The specific role of this calcium in the enzyme mechanism is unknown, though it has been shown to be important for enzymatic activity and thermostability. We report molecular dynamics (MD) simulations of calcium-bound and calcium-free N1 complexes with the inhibitor oseltamivir (marketed as the drug Tamiflu), independently using both the AMBER FF99SB and GROMOS96 force fields, to give structural insight into calcium stabilization of key framework residues. Y347, which demonstrates similar sampling patterns in the simulations of both force fields, is implicated as an important N1 residue that can “clamp” the ligand into a favorable binding pose. Free energy perturbation and thermodynamic integration calculations, using two different force fields, support the importance of Y347 and indicate a +3 to +5 kcal/mol change in the binding free energy of oseltamivir in the absence of calcium. With the important role of structure-based drug design for neuraminidase inhibitors and the growing literature on emerging strains and subtypes, inclusion of this calcium for active site stability is particularly crucial for computational efforts such as homology modeling, virtual screening, and free energy methods. Proteins 2010. © 2010 Wiley-Liss, Inc.
登录
查看更多内容
影响因子：
2.8
作者：
BEUTLER, TC;MARK, AE;VANGUNSTEREN, WF
通讯作者：
VANGUNSTEREN, WF
影响因子：
15
作者：
Amaro RE;Cheng X;Ivanov I;Xu D;McCammon JA
通讯作者：
McCammon JA
影响因子：
2.8
作者：
Du, Qi-Shi;Wang, Shu-Qing;Chou, Kuo-Chen
通讯作者：
Chou, Kuo-Chen
影响因子：
15
作者：
Hamelberg, D;McCammon, JA
通讯作者：
McCammon, JA
影响因子：
3.4
作者：
Aruksakunwong, Ornjira;Malaisree, Maturos;Hannongbua, Supot
通讯作者：
Hannongbua, Supot