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Insights into the structure and dynamics of HIV-1 maturation intermediates and nonuniform sampling methods for magic angle spinning NMR.

机译：深入了解HIV-1成熟中间体的结构和动力学以及魔术角旋转NMR的非均匀采样方法。

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摘要

A key step in the HIV-1 lifecycle is viral maturation, which proceeds through the proteolytic cleavage of the Gag Polyprotein into its constituent domains, including: matrix (MA), capsid (CA), nucleocapsid (NC), P6, and two small spacer peptides, SP1 and SP2. After cleavage, HIV-1 undergoes a dramatic structural rearrangement resulting in the condensation of the conical capsid core and an infectious virus. Viral maturation is a prerequisite for infectivity and has therefore become an attractive target for therapeutic intervention. Atomic-level understanding of the viral maturation mechanism, including critical structural and dynamics details of maturation intermediates and their interactions with maturation inhibitors, is currently lacking.;In this dissertation, assemblies of HIV-1 maturation intermediates are studied by solid-state magic angle spinning NMR spectroscopy. Using this methodology, insights are provided for intermediates representing both early and late stages of maturation. While monitoring interactions between protein assemblies and maturation inhibitors remains challenging, the characterization of maturation intermediates in the assembled state provides an initial framework for future studies aimed to understand viral maturation in its entirety and the viral inhibition mechanism.;NMR is an inherently insensitive technique, and this is a major challenge encountered when studying large protein assemblies by solid-state MAS NMR. Herein, the development and implementation of nonuniform sampling (NUS) methods and alternative data processing protocols are presented. Through the use of exponentially biased NUS schedules considerable inherent sensitivity enhancements on the order of 1.5-2.0 fold per indirect dimension can be obtained without sacrificing resolution. These enhancements were quantified in the frequency domain through the maximum entropy interpolation (MINT) processing, which allows for a linear transformation between the time and frequency domain, even in datasets possessing a high dynamic range. These findings are demonstrated for a variety of biological solids and have enabled the characterization of systems that are limited by their sensitivity.
机译：HIV-1生命周期的关键步骤是病毒成熟，它通过将Gag多蛋白的蛋白水解切割进其组成域，包括：基质（MA），衣壳（CA），核衣壳（NC），P6和两个小蛋白间隔肽SP1和SP2。切割后，HIV-1经历了剧烈的结构重排，导致圆锥形衣壳核心与传染性病毒凝结。病毒成熟是感染力的前提，因此已成为治疗干预的有吸引力的目标。目前尚缺乏对病毒成熟机理的原子层次的了解，包括对成熟中间体的关键结构和动力学细节及其与成熟抑制剂的相互作用的了解；本论文通过固态魔术角研究了HIV-1成熟中间体的组装。旋转核磁共振光谱。使用这种方法，可以提供代表成熟早期和晚期的中间体的见解。虽然监测蛋白质装配体和成熟抑制剂之间的相互作用仍然具有挑战性，但组装状态下成熟中间体的表征为未来研究提供了一个初步框架，旨在了解病毒的整体成熟和病毒抑制机理。NMR是一种固有的不敏感技术，这是通过固态MAS NMR研究大型蛋白质装配体时遇到的主要挑战。本文介绍了非均匀采样（NUS）方法和替代数据处理协议的开发和实现。通过使用指数偏置的NUS计划，可以在不牺牲分辨率的情况下，将每个固有维度的固有灵敏度提高了大约1.5-2.0倍。通过最大熵插值（MINT）处理在频域中对这些增强进行了量化，即使在具有高动态范围的数据集中，也可以在时域和频域之间进行线性变换。这些发现已针对多种生物固体进行了证明，并且能够表征受其敏感性限制的系统。

著录项

  • 作者

    Suiter, Christopher L.;

  • 作者单位

    University of Delaware.;

  • 授予单位 University of Delaware.;
  • 学科 Chemistry.;Biogeochemistry.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 257 p.
  • 总页数 257
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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