来自上海交大生命科学技术学院、美国弗莱德•哈钦森癌症研究中心的研究人员在在A型流感病毒M2跨膜蛋白质子通道分子调控机制的研究中取得重要进展,成果发表在化学领域著名学术期刊《美国化学会志》(Journal of the American Chemical Society)上。
文章的第一作者是上海交大生命科学技术学院的博士生顾若虚,上海交大的魏冬青教授及美国弗莱德?哈钦森癌症研究中心的Limin Angela Liu为这篇文章的共同通讯作者。魏冬青教授的主要研究方向为生物信息学和生物物理学,近年来主要开展结构生物信息学和计算机辅助药物设计的研究工作。至今发表SCI文章100多篇,被累积引用2422次。
2008年《自然》(Nature)杂志曾同时发表了两篇文章,报道了A型流感病毒M2跨膜蛋白质子通道的结构,分别由X-ray和NMR获得,但是配体结合位点则完全不同,一个在通道中间(P-binding site),而另外一个在通道表面靠近C端的位置(S-binding site),这引发了诸多的科学争议。
顾若虚博士在魏冬青教授的指导下采用分子动力学和自由能计算的方法计算了通道的抑制剂金刚乙胺结合到离子通道两个位点处的自由能,发现通道中间的结合位点比通道表面的结合位点从能量上更加稳定,但需要跨越的能垒远远高于结合到通道表面的位点,因此,通道中间的结合位点是热力学位点,对抑制通道起主要作用。通道表面的结合位点是动力学位点,药物更容易结合,同时也更容易解离。这项研究工作解释了上述看似相互矛盾的实验现象,同时有助于阐释药物调控离子通道的机理,对于药物设计有一定的指导作用。(生物谷 Bioon.com)
doi:10.1021/ja1114198
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Free Energy Calculations on the Two Drug Binding Sites in the M2 Proton Channel
Ruo-Xu Gu, Limin Angela Liu, Dong-Qing Wei, Jian-Guo Du, Lei Liu, and Hong Liu
Two alternative binding sites of adamantane-type drugs in the influenza A M2 channel have been suggested, one with the drug binding inside the channel pore and the other with four drug molecule S-binding to the C-terminal surface of the transmembrane domain. Recent computational and experimental studies have suggested that the pore binding site is more energetically favorable but the external surface binding site may also exist. Nonetheless, which drug binding site leads to channel inhibition in vivo and how drug-resistant mutations affect these sites are not completely understood. We applied molecular dynamics simulations and potential of mean force calculations to examine the structures and the free energies associated with these putative drug binding sites in an M2–lipid bilayer system. We found that, at biological pH (7.4), the pore binding site is more thermodynamically favorable than the surface binding site by 7 kcal/mol and, hence, would lead to more stable drug binding and channel inhibition. This result is in excellent agreement with several recent studies. More importantly, a novel finding of ours is that binding to the channel pore requires overcoming a much higher energy barrier of 10 kcal/mol than binding to the C-terminal channel surface, indicating that the latter site is more kinetically favorable. Our study is the first computational work that provides both kinetic and thermodynamic energy information on these drug binding sites. Our results provide a theoretical framework to interpret and reconcile existing and often conflicting results regarding these two binding sites, thus helping to expand our understanding of M2–drug binding, and may help guide the design and screening of novel drugs to combat the virus.