AMBER SIMULATIONS OF HIV-1 PROTEASE AND LIGANDS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 HIV-1蛋白酶是一种篮状病毒酶，参与病毒的成熟。抑制这种酶可以减少感染者体内的病毒载量。虽然目前有几种药物可以抑制艾滋病毒蛋白酶的功能，但随着蛋白酶继续快速突变为耐药形式，设计和开发新的药物的必要性势在必行。20世纪90年代初，弗里德曼和他的同事发表了两份报告，将富勒烯和富勒烯衍生物(巴克球)描述为HIV-1蛋白酶的抑制剂，因为它们的大小和形状恰好适合并抑制活性部位。不幸的是，这项工作没有带来可行的药物，因为碳氢基荞麦球的水溶特性被证明是一个不可逾越的挑战。最近，我们发表了一项关于一类具有不同疏水/亲水性质的新型多面体分子的分子行为的计算研究。在研究这些分子时，我们意识到它们的大小和形状与C60相当，而它们的键的性质使它们更易溶于水。我们对使用这些分子作为HIV-1蛋白酶抑制剂的可行性进行计算机研究很感兴趣。此前，我们已经在OPLS2005/GBSA(水)表面上使用MacroModel(序列)中实现的随机动力学，对没有任何配体的HIV蛋白酶与C60以及与我们的分子络合进行了SD模拟。我们希望使用不同的力场和采样算法来验证我们的结果，因此我们一直在自学如何正确使用琥珀模拟程序包。我们需要300,000个单元，以便在多个处理器上运行琥珀，从而缩短测试和学习时间。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The HIV-1 protease is a basket-shaped viral enzyme that participates in the maturation of the virus. Inhibition of this enzyme reduces the viral load in infected individuals. While several drugs are currently available that inhibit the function of the HIV protease, the need to design and develop new, novel drugs is imperative as the protease continues to rapidly mutate into drug-resistant forms. In the early 1990s Friedman and co-workers published two reports describing fullerene and fullerene derivatives (buckyballs) as inhibitors of HIV-1 protease as they are precisely the right size and shape to fit into and inhibit the active site. Unfortunately, this work did not lead to viable drugs as the aqueous solubility characteristics of the hydrocarbon-based buckyballs proved to be an insurmountable challenge. Recently we have published a computational study of the molecular behavior of an important class of new polyhedral molecules with different hydrophobic/hydrophilic properties. While studying these molecules we realized that their size and shape is quite comparable to C60 while the nature of their bonds allows them to be much more water soluble. We are interested in performing a computational investigation of the feasibility of using these molecules as HIV-1 protease inhibitors. Previously, we have performed SD simulations of the HIV protease sans any ligands; with C60; and in complexation with our molecules, using stochastic dynamics as implemented in MacroModel (serial) on the OPLS2005/GBSA(water) surface. We would like to verify our results using a different force field and sampling algorithm and so we have been teaching ourselves to properly use the AMBER simulation package. We are requesting 30,0000 units in order to run AMBER on multiple processors shortening the testing and learning times.