利用計(jì)算機(jī)模擬(computer simulation)方法來(lái)揭示體內(nèi)最小的構(gòu)建單元(building block)的行為正在幫助科學(xué)家們確定分子在人類疾病中所起的作用,。
在最近的一系列研究中,,來(lái)自澳大利亞莫納什大學(xué)生物醫(yī)學(xué)科學(xué)學(xué)院的研究人員證實(shí)分子運(yùn)動(dòng)和分子相互作用在人體如何患上疾病、檢測(cè)疾病和對(duì)疾病如何作出反應(yīng)方面發(fā)揮著非常重要的作用,。
領(lǐng)導(dǎo)三項(xiàng)研究的副教授Ashley Buckle說(shuō),,他的研究小組利用花費(fèi)數(shù)月時(shí)間在一臺(tái)超級(jí)計(jì)算機(jī)上運(yùn)行的計(jì)算機(jī)模擬方法正揭示出利用純粹實(shí)驗(yàn)技術(shù)不可能檢測(cè)的蛋白的分子“舞蹈(choreography)”,。
副教授 Buckle說(shuō),傳統(tǒng)上,,這個(gè)領(lǐng)域的研究人員利用X射線晶體分析法來(lái)拍攝分子結(jié)構(gòu)的快照,。但是分子之間存在大量瞬間發(fā)生的相互作用。這些相互作用能夠解釋很多蛋白行為和當(dāng)它們產(chǎn)生錯(cuò)誤時(shí)所產(chǎn)生的結(jié)果,。因此,,研究人員需要利用這些實(shí)驗(yàn)數(shù)據(jù)---快照---進(jìn)行外推,并重建分子運(yùn)動(dòng)來(lái)開展深入的研究,。
這三項(xiàng)研究證實(shí)這種新興研究技術(shù)的重要性,。2012年3月8日,發(fā)表在PLoS Computational Biology期刊上的一項(xiàng)研究詳細(xì)描述了免疫系統(tǒng)蛋白的運(yùn)動(dòng)在識(shí)別感染和觸發(fā)免疫應(yīng)答中所發(fā)揮的關(guān)鍵性作用,。<<<相關(guān)論文參見(jiàn)“Epitope Flexibility and Dynamic Footprint Revealed by Molecular Dynamics of a pMHC-TCR Complex”
副教授Buckle說(shuō),,“這種識(shí)別是一種關(guān)鍵性的事件。在此之前,,我們還沒(méi)有充分理解它是如何發(fā)生的,。模擬這些分子如何移動(dòng)能夠加深我們對(duì)此的理解。”
第二項(xiàng)研究也是發(fā)表在PLoS Computational Biology期刊上的,,它解釋了為什么有可能成為一種重要的抗生素作用靶標(biāo)的酶當(dāng)被四個(gè)抗生素分子牢固結(jié)合而不是與一個(gè)抗生素分子不穩(wěn)定結(jié)合時(shí),,也能夠有效地發(fā)揮作用,。理解這種結(jié)構(gòu)可能有助于人們抗發(fā)出對(duì)抗被稱作耐甲氧西林金黃色葡萄球菌(Methicillin Resistant Staphylococcus Aureus, MRSA)的超級(jí)細(xì)菌。<<<相關(guān)論文參見(jiàn)“Structural and Dynamic Requirements for Optimal Activity of the Essential Bacterial Enzyme Dihydrodipicolinate Synthase”
第三項(xiàng)研究于2012年6月20日發(fā)表在Biophysical Journal期刊上, 它解釋了一種導(dǎo)致肝硬化的蛋白突變,。<<相關(guān)論文參見(jiàn)“Conformational Properties of the Disease-Causing Z Variant of α1-Antitrypsin Revealed by Theory and Experiment”
副教授Buckle說(shuō),,“利用X射線晶體分析法,正常的蛋白和發(fā)生突變的蛋白看起來(lái)完全一樣,。當(dāng)我們運(yùn)行計(jì)算機(jī)模擬時(shí),,我們能夠觀察這兩種蛋白分子運(yùn)行方式存在較大的差別。”(生物谷:Bioon.com)
本文編譯自The magic of the movies - molecules in 4D
doi: 10.1016/j.bpj.2012.05.023
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Conformational Properties of the Disease-Causing Z Variant of α1-Antitrypsin Revealed by Theory and Experiment
Itamar Kass▵, Anja S. Knaupp▵, Stephen P. Bottomley and Ashley M. Buckle
The human serine protease inhibitor (serpin) α-1 antitrypsin (α1-AT) protects tissues from proteases of inflammatory cells. The most common disease-causing mutation in α1-AT is the Z-mutation (E342K) that results in an increased propensity of α1-AT to polymerize in the ER of hepatocytes, leading to a lack of secretion into the circulation. The structural consequences of this mutation, however, remain elusive. We report a comparative molecular dynamics investigation of the native states of wild-type and Z α1-AT, revealing a striking contrast between their structures and dynamics in the breach region at the top of β-sheet A, which is closed in the wild-type simulations but open in the Z form. Our findings are consistent with experimental observations, notably the increased solvent exposure of buried residues in the breach region in Z, as well as polymerization via domain swapping, whereby the reactive center loop is rapidly inserted into an open A-sheet before proper folding of the C-terminal β-strands, allowing C-terminal domain swapping with a neighboring molecule. Taken together, our experimental and simulation data imply that mutations at residue 342 that either stabilize an open form of the top of β-sheet A or increase the local flexibility in this region, may favor polymerization and hence aggregation.