Efficiency of Enhanced Sampling Methods in GPCR Research

GPCR 研究中增强采样方法的效率

• 批准号: 8072081
• 负责人: Marta Filizola
• 金额: $ 16.78万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072081
• 关键词: ADRB2 gene; Address; Adrenergic Receptor; Agonist; Algorithms; Amyloid beta-Protein Precursor; Applications Grants; Binding; Binding Sites; Biochemical; C-terminal; Cereals; Collaborations; Coupled; Data; Dimerization; Disease; Docking; Drug Design; Drug Prescriptions; Fluorescence Spectroscopy; Funding; G-Protein-Coupled Receptors; Glycophorin A; Goals; Kinetics; Laboratories; Ligand Binding; Ligands; Literature; Marketing; Membrane Proteins; Methods; Modeling; Molecular; Molecular Conformation; Molecular Models; Mutagenesis; Mutation; Opioid Receptor; Opsin; Pharmaceutical Preparations; Phase; Physiological; Preparation; Research; Research Activity; Resolution; Rhodopsin; Sampling; Source; Structure; System; Testing; Therapeutic; Therapeutic Agents; Transmembrane Domain; Work; base; clinically relevant; computer studies; design; dimer; flexibility; improved; molecular dynamics; molecular modeling; monomer; mutant; novel; public health relevance; receptor; receptor function; simulation

DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCRs) are abundant membrane proteins of extreme pharmacological importance since they are the primary targets for about 30% of prescription drugs that are currently on the market, and are likely to be potential targets for new therapeutic agents. Despite a great deal of research activity in the GPCR field, the design of powerful drugs acting at these receptors has lagged behind due to the limited understanding of the ligand-induced conformational changes of these receptors associated with specific physiological functions. For years, conventional drug design at GPCRs has mainly focused on the inhibition of a single receptor at a usually well-defined ligand-binding site. The growing body of evidence that GPCRs form clinically relevant dimers/oligomers with implications in several disorders has recently added a new complexity to the field, making the understanding of the mechanisms and dynamics governing the interaction between receptor pairs and/or higher-order oligomers equally important for successful rational drug design. The wealth of new higher-resolution structural, biochemical, and biophysical information on GPCRs that has appeared in the recent literature, coupled to recent advancements in coarse-grained modeling and enhanced sampling algorithms, suggests new ways to efficiently explore the conformational space of GPCRs (both monomers and dimers/oligomers), and to generate novel testable hypotheses of molecular mechanisms underlying receptor function. In this grant application, we propose to conduct exploratory metadynamics-based computational studies of ideal membrane protein systems, i.e. ¿-adrenergic receptor, glycophorin A, and the transmembrane domain dimer of the amyloid precursor protein, to validate the efficiency of enhanced sampling methods in predicting ligand-specific activated states and/or dimerization-disrupting mutants that agree with experimental data. PUBLIC HEALTH RELEVANCE: The discovery of powerful therapeutic drugs acting at G-protein coupled receptors (GPCRs), the largest, most versatile, and most pharmaceutically important group of membrane proteins, has been impaired over the years by the limited understanding of the molecular mechanisms underlying their diverse functions. The overall goal of the work proposed in this grant application is to explore the extent to which advanced computational strategies using enhanced sampling methods can improve dynamic molecular models of GPCRs, and generate novel testable hypotheses of functional modulation to pursue rational drug design successfully.

描述（由适用提供）：G蛋白偶联受体（GPCR）是极端药理重要性的丰富膜蛋白，因为它们是目前市场上大约30％的处方药的主要靶标，并且可能是新治疗剂的潜在靶标。尽管在GPCR领域进行了大量的研究活动，但由于对配体引起的与特定物理功能相关的这些受体的会议变化的限制，对这些受体作用的强大药物的设计却落后了。多年来，GPCRS的常规药物设计主要集中在通常定义明确的配体结合部位的单个受体上。越来越多的证据表明，GPCR形成临床相关的二聚体/低聚物，对几种疾病产生了影响，这使该领域增加了新的复杂性，从而了解了对受体对和/或高级寡聚物之间相互作用的机制和动态的理解，对于成功的合理药物设计也同样重要。最近出现在最近文献中出现的有关GPCR的新的高分辨率结构，生化和生物物理信息的财富，并与粗粒的建模和增强取样算法的最新进步相结合，提出了有效探索GPCR（MOLEC/OLIGERS/OLIGERS）的新方法，并提出了新的方法，并探索了GPCR的会议空间，并探索了Molecers/mol oberation noceration Nofical selforation Nofical selforation Nexportation Gractory obles groperation Noficals），以及多种多样的新方法）。基础受体功能。在此赠款应用中，我们建议对理想膜蛋白系统的基于探索性金属的计算研究，即 - 肾上腺肾上腺素，糖蛋白A和淀粉样蛋白前体蛋白的跨膜结构域二聚体，以验证增强的实验性调查效率和/或或降解的效率。 公共卫生相关性：在G蛋白偶联受体（GPCRS）中发现强大的治疗药物，这是多年来，最大，最广泛，最重要，最重要的膜蛋白组的最大，最通用，最重要的膜蛋白质组受到了对分子机制的有限理解，从而受到了损害。本赠款应用中提出的工作的总体目标是探索使用增强采样方法的先进计算策略在多大程度上可以改善GPCR的动态分子模型，并生成新颖的功能调节功能调制假设，以成功地成功地进行理性药物设计。

项目成果

Molecular determinants and thermodynamics of the amyloid precursor protein transmembrane domain implicated in Alzheimer's disease.

• DOI: 10.1016/j.jmb.2011.03.028
• 发表时间: 2011-05-20
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Wang H;Barreyro L;Provasi D;Djemil I;Torres-Arancivia C;Filizola M;Ubarretxena-Belandia I
• 通讯作者: Ubarretxena-Belandia I