Macromolecular Conformational Heterogeneity

大分子构象异质性

• 批准号: 9920168
• 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/9920168
• 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; Malignant Neoplasms; Metals; Methods; Modeling; Molecular Conformation; Nucleic Acids; Oligonucleotides; Pharmaceutical Preparations; Polysaccharides; Property; Proteins; Pseudomonas; RNA; Research; Sampling; Specificity; Structure; System; Therapeutic; Vaccine Antigen; Vaccines; Work; antibiotic resistant infections; base; cancer immunotherapy; drug development; 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.

项目摘要 生物大分子表现出惊人的构象异质性，这是它们 各种功能。这种异质性的重要性正变得越来越明显，因为不同的生物 识别与单个生物分子的各种构象状态相关的功能。至 研究大分子的构象性质，促进信息在药物中的应用 在开发过程中，我们的实验室专注于全面的研究计划，优化和扩展 生物和类药物分子的经验力场，开发新的构象和溶质 抽样方法，并将这些工具应用于与治疗相关的系统的协作研究。在 建议的研究我们将进一步优化和推广添加剂(固定电荷)CHARMM和 可极化经典德鲁德振子力场。德鲁德力场的工作将涉及扩展到 涵盖了全方位的生物大分子和有机、类药物分子，不断完善 模型的整体精度，扩展模型以通过包含局部 电荷转移效应，并实施改进的方法来处理范德华相互作用。 采样方法的发展将扩展哈密顿复本交换方法以增强采样 在寡核苷酸和多糖中，包括相关特定自由度的改进采样 具有使用偏置电势的高能势垒。本实验室研制的溶质采样法 基于振荡μEX巨正则蒙特卡罗/分子动力学方法将推广到 更准确地采样渗透分子和离子的分布，包括大分子和 允许该方法与可极化的Drude力场一起使用。结合起来，构象和 溶质采样方法是一种强大的方法，它将使理论研究成为可能 环境和大分子构象异质性之间的相互作用。开发的工具将是 利用溶剂消色移在研究DNA离子气氛的核酸研究中的应用 用QM/MM方法测定了Mg+2对RNA构象异质性的影响， 包括细菌病原体中的核糖体和小调控RNA，以及催化和碱基 DNA糖基酶对碱基切除修复重要的特异性机制。在多糖领域， 多聚糖作为抗生素耐药疫苗抗原的构象异质性 将对细菌和用于癌症免疫治疗的药物进行调查。要针对的特定疾病状态包括 肺炎克雷伯菌、铜绿假单胞菌和癌症相关耐药感染 可接受免疫疗法治疗。此外，这些合作努力将进一步验证 制定了可供科学界使用并被科学界广泛使用的力场和方法、工具。