來(lái)自上海交大生命科學(xué)技術(shù)學(xué)院,、美國(guó)弗萊德•哈欽森癌癥研究中心的研究人員在在A型流感病毒M2跨膜蛋白質(zhì)子通道分子調(diào)控機(jī)制的研究中取得重要進(jìn)展,，成果發(fā)表在化學(xué)領(lǐng)域著名學(xué)術(shù)期刊《美國(guó)化學(xué)會(huì)志》（Journal of the American Chemical Society）上。
文章的第一作者是上海交大生命科學(xué)技術(shù)學(xué)院的博士生顧若虛,，上海交大的魏冬青教授及美國(guó)弗萊德?哈欽森癌癥研究中心的Limin Angela Liu為這篇文章的共同通訊作者。魏冬青教授的主要研究方向?yàn)樯镄畔W(xué)和生物物理學(xué),，近年來(lái)主要開(kāi)展結(jié)構(gòu)生物信息學(xué)和計(jì)算機(jī)輔助藥物設(shè)計(jì)的研究工作,。至今發(fā)表SCI文章100多篇，被累積引用2422次,。
2008年《自然》（Nature）雜志曾同時(shí)發(fā)表了兩篇文章,，報(bào)道了A型流感病毒M2跨膜蛋白質(zhì)子通道的結(jié)構(gòu)，分別由X-ray和NMR獲得,，但是配體結(jié)合位點(diǎn)則完全不同,，一個(gè)在通道中間（P-binding site），而另外一個(gè)在通道表面靠近C端的位置（S-binding site),，這引發(fā)了諸多的科學(xué)爭(zhēng)議,。
顧若虛博士在魏冬青教授的指導(dǎo)下采用分子動(dòng)力學(xué)和自由能計(jì)算的方法計(jì)算了通道的抑制劑金剛乙胺結(jié)合到離子通道兩個(gè)位點(diǎn)處的自由能，發(fā)現(xiàn)通道中間的結(jié)合位點(diǎn)比通道表面的結(jié)合位點(diǎn)從能量上更加穩(wěn)定,，但需要跨越的能壘遠(yuǎn)遠(yuǎn)高于結(jié)合到通道表面的位點(diǎn),，因此，通道中間的結(jié)合位點(diǎn)是熱力學(xué)位點(diǎn),，對(duì)抑制通道起主要作用,。通道表面的結(jié)合位點(diǎn)是動(dòng)力學(xué)位點(diǎn)，藥物更容易結(jié)合,，同時(shí)也更容易解離,。這項(xiàng)研究工作解釋了上述看似相互矛盾的實(shí)驗(yàn)現(xiàn)象，同時(shí)有助于闡釋藥物調(diào)控離子通道的機(jī)理，對(duì)于藥物設(shè)計(jì)有一定的指導(dǎo)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.
