Characterizing loop dynamics and ligand recognition in human- and avian-type influenza neuraminidases via generalized born molecular dynamics and end-point free energy calculations.
Characterizing loop dynamics and ligand recognition in human- and avian-type influenza neuraminidases via generalized born molecular dynamics and end-point free energy calculations.
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DOI：
10.1021/ja8085643
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发表时间：
2009-04-08
影响因子：
15
通讯作者：
McCammon JA
中科院分区：
文献类型：
--
作者：
Amaro RE;Cheng X;Ivanov I;Xu D;McCammon JA
组1和组2致病性甲型流感亚型神经氨酸酶（NA）酶的比较动力学和抑制剂结合自由能具有基本的生物学意义，并与基于结构的抗病毒化合物药物设计研究相关。在这项工作中，我们提出了禽（N1）和人（N9）型NAs的7个广义Born分子动力学模拟，以探索两种亚型的相对灵活性，无论是否结合抑制剂奥司他韦。通过隐式溶剂处理获得的增强采样对两种亚型的动力学提出了一些具有挑战性的见解，包括2组酶可能在430结合位点区域表现出相似的运动，但不同的150环运动。终点自由能计算阐明了对抑制剂结合自由能的贡献，并表明在比较不同亚型时不能忽略熵的考虑。我们预计这里提出的发现将对开发针对季节性和大流行性流感毒株的新型抗病毒化合物具有广泛的意义。
The comparative dynamics and inhibitor binding free energies of group-1 and group-2 pathogenic influenza A subtype neuraminidase (NA) enzymes are of fundamental biological interest and relevant to structure-based drug design studies for antiviral compounds. In this work, we present seven generalized Born molecular dynamics simulations of avian (N1)- and human (N9)-type NAs in order to probe the comparative flexibility of the two subtypes, both with and without the inhibitor oseltamivir bound. The enhanced sampling obtained through the implicit solvent treatment suggests several provocative insights into the dynamics of the two subtypes, including that the group-2 enzymes may exhibit similar motion in the 430-binding site regions but different 150-loop motion. End-point free energy calculations elucidate the contributions to inhibitor binding free energies and suggest that entropic considerations cannot be neglected when comparing across the subtypes. We anticipate the findings presented here will have broad implications for the development of novel antiviral compounds against both seasonal and pandemic influenza strains.
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影响因子：
3
作者：
Landon, Melissa R.;Amaro, Rommie E.;Baron, Riccardo;Ngan, Chi Ho;Ozonoff, David;McCammon, J. Andrew;Vajda, Sandor
通讯作者：
Vajda, Sandor
DOI：
10.1073/pnas.062398499
发表时间：
2002-04-02
影响因子：
11.1
作者：
Dennis, S;Kortvelyesi, T;Vajda, S
通讯作者：
Vajda, S
影响因子：
7.6
作者：
Carr, J;Ives, J;Roberts, N
通讯作者：
Roberts, N
影响因子：
4.9
作者：
Gubareva, LV;Webster, RG;Hayden, FG
通讯作者：
Hayden, FG
影响因子：
4.9
作者：
Govorkova, EA;Leneva, IA;Webster, RG
通讯作者：
Webster, RG