MOLECULAR DYNAMICS STUDIES OF MUTANT HIV GP120 ENVELOP PROTEINS WITH BOUND HIV

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 这个计算项目的主要目标是合理地设计小分子拮抗剂，阻断人类CD 4细胞表面受体和HIV-1的gp 120包膜蛋白之间的相互作用，作为治疗艾滋病的潜在疗法。病毒包膜蛋白gp 120在与细胞CD 4受体结合后发生大的构象变化，从而允许随后与趋化因子受体结合和病毒-宿主细胞融合1。NIH PO 1 GM 56550项目组（细胞进入中HIV-1包膜功能的基于结构的拮抗作用）合成并测定了一系列NBD化合物类似物2。这些化合物与CD 4竞争结合gp 12，并以类似于CD 4结合的方式诱导gp 120的结构化3。这类化合物的预测结合模式已产生的计算对接研究和验证突变分析4。在启动电流分配的过程中，琥珀色9.09。基于PSC的大本钟簇的分子动力学已被用于探索抑制剂NBD 556结合野生型和gp 120包膜的各种突变的动态波动。分子动力学轨迹分析表明，四甲基哌啶基团的不对称蛋白质-配体相互作用。这表明四甲基基团可以被合成修饰而对结合亲和力没有负面影响。野生型和突变蛋白-配体复合物的轨迹也用于使用在AMBER中实施的MM/GBSA 9，10方法预测结合亲和力。这些计算目前正在使用2009年4月到期的启动拨款进行。目前的MAC提案要求Pople上的计算资源继续使用最新版本（10）的AMBER进行分子动力学和MM/GBSA计算，该版本具有最近解决的晶体结构。该请求还包括用于安装ROCS基于形状的虚拟筛选软件6 -8以发现新化合物的资源。中等分配将为完成新型NBD化合物的化合物设计周期所需的五个计算步骤提供资源。这些计算是：1）使用AMBER/MM-GBSA对现有化合物产生预测的结合亲和力与测量的结合亲和力的相关性图2）产生化合物和muplant-gp 120对的计算的和实验的结合亲和力之间的相关性3）分析化合物和muplant-gp 120对的蛋白质-配体相互作用以确定gp 120和小分子的哪些区域可能增强结合亲和力4）使用Zinc 11数据库的基于ROCS的相似性搜索来识别新化合物，其封装新化学型和相互作用5）使用AMBER/MM-GBSA方法来在合成之前预测新抑制剂的结合亲和力。使用Pople版本的AMBER 10.0进行分子动力学和ROCS虚拟筛选的快速翻转将极大地增强基于结构的HIV进入抑制剂设计过程。

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 key objective of this computational project is to rationally design small-molecule antagonists that block the interaction between the human CD4 cell-surface receptor and the gp120 envelop protein of HIV-1 as potential therapeutics for the treatment of AIDS. The viral envelop protein, gp120, undergoes a large conformational change upon binding to the cellular CD4 receptor allowing subsequent binding to the chemokine receptor and viral-host cell fusion1. The NIH PO1 GM 56550 project team (Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry) has synthesized and assayed a series of NBD compound analogs 2. These compounds compete with CD4 binding to gp12 and induces structuring of gp120 in a manner similar to CD4 binding3. A predicted binding mode for this class of compounds has been produced from computational docking studies and verified with mutational analysis4 . Over the course of the start-up current allocation AMBER 9.09. based molecular dynamics on PSC's Big Ben cluster has been used to explore the dynamic fluctuations of the inhibitor NBD556 bound to wild type and various mutations of the gp120 envelope. Analysis of the molecular dynamics trajectories indicates an asymmetric protein-ligand interactions of the tetramethyl piperidine groups. This suggests that the tetramethyl groups can be synthetically modified without negative impact to binding affinity. The trajectories of the wild-type and mutant proteins-ligand complexes are also being used to predict binding affinity using the MM/GBSA9, 10 methodology as implemented in AMBER. These calculations are currently underway using the start-up allocation which expires in April, 2009. The current MAC proposal requests computational resources on Pople to continue molecular dynamics and MM/GBSA calculations using the latest version (10) of AMBER with a recently solved crystal structure. The request also includes resource for installation of the ROCS shape-based virtual screening software6-8 for discovery of novel compounds. A medium allocation will provide resource for the five computational steps necessary to complete a compound design cycle for novel NBD compounds. These calculations are: 1) Produce a correlation plot of predicted verses measured binding affinities using AMBER/MM-GBSA for existing compounds 2) Generate correlations between calculated and experimental binding affinities of compound and mutant-gp120 pairs 3) Analyze protein-ligand interactions of compound and mutant-gp120 pairs to ascertain which regions of gp120 and the small molecule are likely to enhance binding affinity 4) Identify novel compounds using the ROCS based similarity search of the Zinc11 database that encapsulate new chemotypes and interactions 5) Use the AMBER/MM-GBSA methodology to predict binding affinity of novel inhibitors prior to synthesis. Rapid turn-over using the Pople version of AMBER 10.0 for molecular dynamics with ROCS virtual screening would greatly enhance the structure-based design process of HIV entry inhibitors.