Macromolecular Conformational Heterogeneity

大分子构象异质性

• 批准号: 10596535
• 负责人: ALEXANDER D MACKERELL
• 金额: $ 72.3万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596535
• 关键词: Amaze; Area; Atmosphere; Bacterial Antibiotic Resistance; Bacterial Infections; Base Excision Repairs; Biological; Biological Process; Carbohydrates; Charge; Communities; DNA; DNA glycosylase; Development; Disease; Environment; Exhibits; Freedom; Heterogeneity; Immunotherapy; Individual; Investigation; Ions; Klebsiella pneumoniae; Laboratories; Ligation; Malignant Neoplasms; Metals; Methods; Modeling; Molecular Conformation; Nucleic Acids; Oligonucleotides; Polysaccharides; Property; Proteins; Pseudomonas; RNA; Research; Sampling; Specificity; System; Therapeutic; Vaccine Antigen; Vaccines; Work; antibiotic resistant infections; base; cancer immunotherapy; drug development; drug-like compound; improved; macromolecule; method development; molecular dynamics; novel; novel therapeutics; pathogenic bacteria; programs; public health relevance; small molecule therapeutics; solute; tool

Project Summary Biological macromolecules exhibit an amazing degree of conformational heterogeneity as required for their various functions. The importance of this heterogeneity is becoming more evident as different biological functions associated with various conformational states of individual biological molecules are identified. To investigate the conformational properties of macromolecules and facilitate the use of the information in drug development, our laboratory has focused on a comprehensive research program that optimizes and extends empirical force fields for biological and drug-like molecules, develops novel conformational and solute sampling methods and applies those tools in collaborative studies on systems of therapeutic relevance. In the proposed studies we will further optimize and extend both the additive (fixed-charge) CHARMM and polarizable classical Drude oscillator force fields. Work on the Drude force field will involve extensions to cover the full range of biological macromolecules and organic, drug-like molecules, continue to improve the overall accuracy of the model, extend the model to more accurately treat ligated metals via the inclusion of local charge transfer effects and implement improved methods for the treatment of van der Waals interactions. Sampling methods development will extend the Hamiltonian Replica Exchange approach to enhance sampling in oligonucleotides and polysaccharides including improved sampling of specific degrees of freedom associated with high-energy barriers using biasing potentials. The solute sampling method developed in our laboratory based on the oscillating μex Grand-Canonical Monte Carlo/Molecular Dynamics method will be extended to more accurately sample the distribution of osmolytes and ions, including Mg+2, around macromolecules and allow the approach to be used with the polarizable Drude force field. In combination, the conformational and solute sampling approaches represent powerful methods that will allow for theoretical investigations of the interplay between environment and macromolecular conformational heterogeneity. The developed tools will be applied in studies on nucleic acids investigating the ionic atmosphere of DNA, exploiting solvachromatic shifts determined using QM/MM methods, the impact of Mg+2 on the conformational heterogeneity of RNA, including on riboswtiches and small regulatory RNAs in bacterial pathogens, and the catalytic and base specificity mechanisms of DNA glycosylases important for base excision repair. In the area of polysaccharides, the conformational heterogeneity of glycans acting as antigens for vaccines targeting antibiotic resistant bacteria and for use in cancer immunotherapy will be investigated. Specific disease states to be targeted include antibiotic resistant infections associated with Klebsiella Pneumonia and Pseudomonas Aeruginsa and cancers accessible to immunotherapy treatment. In addition, these collaborative efforts will further validate the developed force fields and methods, tools that are available to and widely used by the scientific community.

项目概要 生物大分子表现出惊人程度的构象异质性，这是其生命所需要的。 随着不同的生物功能，这种异质性的重要性变得越来越明显。 鉴定了与单个生物分子的各种构象状态相关的功能。 研究大分子的构象特性并促进信息在药物中的使用 发展，我们的实验室专注于优化和扩展的综合研究计划 生物和药物分子的经验力场，开发新的构象和溶质 采样方法并将这些工具应用于治疗相关系统的合作研究。 拟议的研究，我们将进一步优化和扩展附加（固定电荷）CHARMM 和 极化经典德鲁德振子力场的研究将涉及对德鲁德力场的扩展。 覆盖全系列生物大分子及有机、类药分子，持续完善 模型的整体准确性，通过包含局部数据来扩展模型以更准确地处理连接金属 电荷转移效应并实施改进的方法来处理范德华相互作用。 采样方法的开发将扩展哈密顿副本交换方法以增强采样 在寡核苷酸和多糖中，包括改进相关特定自由度的采样 我们实验室开发的溶质取样方法具有高能垒。 基于振荡 μex 大正则蒙特卡罗/分子动力学方法将扩展到 更准确地采样大分子周围渗透剂和离子（包括 Mg+2）的分布， 允许该方法与极化德鲁德力场结合使用，构象和 溶质取样方法代表了强大的方法，可以对溶质进行理论研究 开发的工具将是环境与大分子构象异质性之间的相互作用。 应用于核酸研究，研究 DNA 的离子气氛，利用溶剂色差位移 使用QM/MM方法确定Mg+2对RNA构象异质性的影响， 包括细菌病原体中的核糖开关和小调节 RNA，以及催化和碱基 DNA糖基化酶的特异性机制对于多糖领域的碱基切除修复很重要， 作为抗生素抗性疫苗抗原的聚糖的构象异质性 将研究细菌和用于癌症免疫治疗的具体疾病状态包括。 与肺炎克雷伯氏菌、铜绿假单胞菌和癌症相关的抗生素耐药性感染 此外，这些合作努力将进一步验证 开发了科学界可用并广泛使用的力场和方法、工具。