2012年12月4日讯 /生物谷BIOON/ --西班牙IMIM研究所及庞培法布拉大学（Pompeu Fabra University，UPF）的生物信息学家已利用分子模拟技术来解释HIV病毒粒子成熟过程的每一个具体步骤，例如，新形成的惰性病毒颗粒如何成为感染性病毒，这对于了解病毒复制至关重要。该项研究已在线发表于《美国国家科学院报》（PNAS）。相关研究成果可能对未来抗逆转录病毒药物的设计非常重要。
HIV病毒颗粒成熟并变得具有感染性，是一种名为HIV蛋白酶的蛋白作用结果。这种蛋白的作用就像一把剪刀，剪断连接蛋白的长链，使新形成的HIV病毒颗粒具有感染性的结构。根据IMIM-UPF计算生物物理小组，整个HIV病毒成熟过程中最引人瞩目的方面之一是，如何释放HIV蛋白酶，例如，这种剪刀蛋白的首次出现，因为它最初也是组成新HIV病毒粒子的长聚蛋白链的一部分。
利用ACEMD的一个分子模拟软件及技术，该研究小组已经证明，首个剪刀蛋白可从内聚蛋白连的中间切断自身，它们是通过结合其N端至自身的激活位点，随后切断它们与其余链之间的化学键。这是整个HIV成熟过程的初始步骤。如果HIV蛋白酶能在成熟过程中被中止，将能够阻止病毒颗粒的成熟及变得具有传染性。
该项工作利用GPUGRID.net开展，这是一个自愿分布式计算平台。研究人员利用这种强大的计算能力来处理大量的数据，并生成高度复杂的分子模拟。
研究人员称，HIV病毒成熟过程中的这一发现，为未来利用这些新分子机制的药物设计奠定了基础。当前，这项工作提供了对HIV生命周期一个关键步骤的更深入了解。（生物谷bioon.com）
编译自：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.
