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.

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。 这个计算项目的关键目标是合理地设计小分子拮抗剂，阻断人类CD4细胞表面受体和HIV-1的gp120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gp120在与细胞内的CD4受体结合后会发生很大的构象变化，从而允许随后与趋化因子受体和病毒-宿主细胞融合1结合。NIH PO1 GM 56550项目小组(基于结构的HIV-1外膜功能在细胞进入中的拮抗作用)合成并检测了一系列NBD类似物2。这些化合物与gp12结合的c4竞争，以类似c4结合的方式诱导gp120的结构。这类化合物的预测结合模式已经从计算对接研究中产生，并用突变分析4进行了验证。在启动过程中电流分配为琥珀9.09。基于PSC的大本钟簇的分子动力学，研究了野生型结合的抑制剂NBD556的动态变化以及gp120外膜的各种突变。分子动力学轨迹分析表明，四甲基哌啶基团之间存在不对称的蛋白质-配体相互作用。这表明可以对四甲基进行合成修饰，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体的轨迹也被用来预测结合亲和力，使用在琥珀公司实施的MM/GBSA9，10方法。目前正在使用2009年4月到期的启动拨款进行这些计算。目前的MAC提案要求Pople上的计算资源继续使用具有最近解算的晶体结构的最新版本(10)的琥珀进行分子动力学和MM/GBSA计算。申请还包括安装基于ROCs形状的虚拟筛选软件6-8以发现新化合物的资源。介质分配将为完成新型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对现有化合物的预测结合亲和力与测量的结合亲和力之间的关联图2)生成化合物和突变-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-gp120对的蛋白质-配体相互作用，以确定gp120的哪些区域和小分子可能增强结合亲和力4)使用Zinc11数据库的基于ROCS的相似性搜索来鉴定包含新化学类型和相互作用的新化合物5)在合成之前使用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虚拟筛选的快速翻转将极大地增强HIV进入抑制剂的基于结构的设计过程。