2012年12月4日訊 /生物谷BIOON/ --西班牙IMIM研究所及龐培法布拉大學(xué)（Pompeu Fabra University,，UPF）的生物信息學(xué)家已利用分子模擬技術(shù)來解釋HIV病毒粒子成熟過程的每一個具體步驟，例如,，新形成的惰性病毒顆粒如何成為感染性病毒,，這對于了解病毒復(fù)制至關(guān)重要。該項研究已在線發(fā)表于《美國國家科學(xué)院報》（PNAS）,。相關(guān)研究成果可能對未來抗逆轉(zhuǎn)錄病毒藥物的設(shè)計非常重要,。
HIV病毒顆粒成熟并變得具有感染性，是一種名為HIV蛋白酶的蛋白作用結(jié)果,。這種蛋白的作用就像一把剪刀,，剪斷連接蛋白的長鏈，使新形成的HIV病毒顆粒具有感染性的結(jié)構(gòu),。根據(jù)IMIM-UPF計算生物物理小組,，整個HIV病毒成熟過程中最引人矚目的方面之一是，如何釋放HIV蛋白酶,，例如,，這種剪刀蛋白的首次出現(xiàn)，因為它最初也是組成新HIV病毒粒子的長聚蛋白鏈的一部分,。
利用ACEMD的一個分子模擬軟件及技術(shù),，該研究小組已經(jīng)證明，首個剪刀蛋白可從內(nèi)聚蛋白連的中間切斷自身,，它們是通過結(jié)合其N端至自身的激活位點,，隨后切斷它們與其余鏈之間的化學(xué)鍵。這是整個HIV成熟過程的初始步驟,。如果HIV蛋白酶能在成熟過程中被中止,，將能夠阻止病毒顆粒的成熟及變得具有傳染性。
該項工作利用GPUGRID.net開展,，這是一個自愿分布式計算平臺,。研究人員利用這種強(qiáng)大的計算能力來處理大量的數(shù)據(jù)，并生成高度復(fù)雜的分子模擬,。
研究人員稱,，HIV病毒成熟過程中的這一發(fā)現(xiàn)，為未來利用這些新分子機(jī)制的藥物設(shè)計奠定了基礎(chǔ),。當(dāng)前,，這項工作提供了對HIV生命周期一個關(guān)鍵步驟的更深入了解,。（生物谷bioon.com）
編譯自：Crucial step in AIDS virus maturation simulated for first time
doi:10.1073/pnas.1210983109
PMC:
PMID:
Kinetic characterization of the critical step in HIV-1 protease maturation
S. Kashif Sadiqa, Frank Noeb, and Gianni De Fabritiis
Abstract：HIV maturation requires multiple cleavage of long polyprotein chains into functional proteins that include the viral protease itself. Initial cleavage by the protease dimer occurs from within these precursors, and yet only a single protease monomer is embedded in each polyprotein chain. Self-activation has been proposed to start from a partially dimerized protease formed from monomers of different chains binding its own N termini by self-association to the active site, but a complete structural understanding of this critical step in HIV maturation is missing. Here, we captured the critical self-association of immature HIV-1 protease to its extended amino-terminal recognition motif using large-scale molecular dynamics simulations, thus confirming the postulated intramolecular mechanism in atomic detail. We show that self-association to a catalytically viable state requires structural cooperativity of the flexible β-hairpin “flap” regions of the enzyme and that the major transition pathway is first via self-association in the semiopen/open enzyme states, followed by enzyme conformational transition into a catalytically viable closed state. Furthermore, partial N-terminal threading can play a role in self-association, whereas wide opening of the flaps in concert with self-association is not observed. We estimate the association rate constant (kon) to be on the order of ∼1 × 104 s−1, suggesting that N-terminal self-association is not the rate-limiting step in the process. The shown mechanism also provides an interesting example of molecular conformational transitions along the association pathway.
