Macromolecular Conformational Heterogeneity

项目摘要 生物大分子表现出惊人程度的构象异质性，这是其生物学特性所需的。 各种功能。这种异质性的重要性正变得越来越明显， 鉴定了与各个生物分子的各种构象状态相关的功能。到 研究大分子的构象性质，促进药物信息的使用 发展，我们的实验室专注于一个全面的研究计划，优化和扩展 生物和药物类分子的经验力场，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性系统的合作研究。在 建议的研究，我们将进一步优化和扩展添加剂（固定电荷）CHARMM和 可极化的经典德鲁德振子力场关于德鲁德力场的工作将涉及扩大 涵盖生物大分子和有机、类药物分子的全系列，不断完善 模型的整体准确性，通过包含局部 电荷转移效应，并实施用于处理货车德瓦尔斯相互作用的改进方法。 采样方法的开发将扩展哈密尔顿矩阵交换方法，以增强采样 在寡核苷酸和多糖中， 具有使用偏置电势的高能量势垒。本实验室开发的溶质取样方法 基于振荡μex巨正则蒙特卡罗/分子动力学方法将扩展到 更准确地采样渗透压物质和离子（包括Mg+2）在大分子周围的分布， 允许该方法用于可极化的德鲁德力场。在组合中，构象和 溶质采样方法代表了强大的方法，将允许理论研究的 环境和大分子构象异质性之间相互作用。开发的工具将是 应用于核酸研究，研究DNA的离子气氛，利用溶剂变色位移 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核酸和小的调节RNA，以及细菌病原体中的催化和碱基 DNA糖基化酶对碱基切除修复的特异性机制。在多糖领域， 用作靶向抗生素抗性疫苗的抗原的聚糖的构象异质性 细菌和用于癌症免疫治疗将被研究。要针对的具体疾病状态包括 与肺炎克雷伯菌和铜绿假单胞菌和癌症相关的抗生素耐药感染 接受免疫治疗。此外，这些合作努力将进一步验证 开发了力场和方法，科学界可以使用并广泛使用的工具。

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.