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

突变型 HIV GP120 包膜蛋白与 HIV 结合的分子动力学研究

• 批准号: 7956364
• 负责人: JUDITH LALONDE
• 金额: $ 0.06万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956364
• 关键词: Acquired Immunodeficiency Syndrome; Affinity; Amber; Binding; Biological Assay; Biomedical Research; CD4 Antigens; CD4 Positive T Lymphocytes; Cell Surface Receptors; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Databases; Docking; Encapsulated; Funding; Grant; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV-1; High Performance Computing; Human; Institution; Ligands; Measures; Methodology; Mutation; Process; Proteins; Request for Proposals; Research; Research Personnel; Resources; Screening procedure; Series; Shapes; Source; Structure; Therapeutic; United States National Institutes of Health; Viral; analog; base; chemokine receptor; computing resources; design; inhibitor/antagonist; molecular dynamics; mutant; novel; piperidine; small molecule; virtual

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该计算项目的主要目标是合理设计小分子拮抗剂，阻断人类 CD4 细胞表面受体与 HIV-1 gp120 包膜蛋白之间的相互作用，作为治疗 AIDS 的潜在疗法。病毒包膜蛋白 gp120 在与细胞 CD4 受体结合后会发生较大的构象变化，从而随后与趋化因子受体结合并实现病毒-宿主细胞融合1。 NIH PO1 GM 56550 项目团队（细胞进入中 HIV-1 包膜功能的基于结构的拮抗）合成并分析了一系列 NBD 化合物类似物 2。这些化合物与 CD4 与 gp12 的结合竞争，并以某种方式诱导 gp120 的结构化类似于 CD4 结合3。此类化合物的预测结合模式已通过计算对接研究产生，并通过突变分析进行验证4。在启动过程中，电流分配为 AMBER 9.09。基于 PSC Big Ben 簇的分子动力学已被用于探索与野生型和 gp120 包膜的各种突变结合的抑制剂 NBD556 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不会对结合亲和力产生负面影响。野生型和突变型蛋白质-配体复合物的轨迹也被用于使用 AMBER 中实施的 MM/GBSA9, 10 方法来预测结合亲和力。这些计算目前正在使用 2009 年 4 月到期的启动分配进行中。当前的 MAC 提案请求 Pople 上的计算资源，以使用最新版本 (10) 的 AMBER 和最近解决的晶体继续进行分子动力学和 MM/GBSA 计算结构。该请求还包括安装用于发现新型化合物的 ROCS 基于形状的虚拟筛选软件 6-8 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 对现有化合物生成预测与测量的结合亲和力的相关图 2) 生成化合物和突变体-gp120 对的计算和实验结合亲和力之间的相关性 3) 分析化合物和突变体 gp120 对，以确定 gp120 和小分子的哪些区域可能增强结合亲和力 4) 使用基于 ROCS 的相似性搜索来识别新化合物封装新化学型和相互作用的 Zinc11 数据库 5) 在合成前使用 AMBER/MM-GBSA 方法预测新型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 虚拟筛选的快速周转将大大增强 HIV 进入抑制剂的基于结构的设计过程。