Exploring Electronic Polarization in Biomolecular Folding and Interactions

项目总结 水溶液中蛋白质、核酸和脂质中蛋白质构象变化的驱动力 膜的特性仍然不完全。理论方法非常适合于建立关系 结构和能量学之间的关系，为确定潜在的生物作用力提供关键信息 在不同的细胞微环境中的过程。我们的实验室使用分子动力学(MD)模拟 用新近发展的Drude极化力场研究模型的构象系综 多肽和蛋白质、核酸和脂膜。在本申请中，我们提出了一个研究计划 这在探索(1)驱动淀粉样多肽与和展开的作用力方面开辟了新的天地 没有翻译后修饰，(2)离子和非正则相互作用在稳定DNA中的作用 G-四链体(Gq)，以及(3)诱导电子极化对小分子分配和 磷脂膜中肽的折叠。这些项目的统一主题是对 原子论细节驱动构象变化，特别强调诱导电子的作用 极化。在项目期间，我们建议研究几个构象集合 致淀粉样多肽了解诱导电子极化对多肽和多肽的作用 水的相互作用(氢键、静电碰撞和其他诱导的偶极-偶极相互作用)。 类似地，我们将研究具有不同折叠(平行、反平行和混合)的DNA GQ，以表征如何 它们的碱基性质(排列、偶极矩等)和环状构象系综受到影响 通过不同的单价离子以及稳定GQ的非正则碱-碱和碱-磷相互作用。 最后的项目包括模拟脂膜中的多肽和小分子，以了解 分配、热力学和氢键的强度以及其他多肽和分子间 膜疏水核心中的相互作用，因为这些相互作用与膜的极性有关 周围的媒介。五年项目期的具体目标是：(1)确定 决定构象变化的淀粉样多肽中的氨基酸，(2)表征相对的 离子、水和非正则碱基相互作用在稳定DNA GQ中的贡献，以及(3)对自由基团的量化 与膜中多肽折叠和小分子分配相关的能量变化。这些项目 代表了研究方案的总体愿景，将严谨的理论方法运用到复杂的 了解各种疾病(包括神经退行性疾病)的分子基础的生物分子 和几种类型的癌症)，并使用所得到的信息来进行计算机辅助药物设计 具有目前最先进的模拟模型的新生物分子靶标。

PROJECT SUMMARY The forces driving conformational change of proteins and nucleic acids in aqueous solution and proteins in lipid membranes remain incompletely characterized. Theoretical methods are well suited to establishing relationships between structure and energetics, providing critical information for determining the forces underlying biological processes in different cellular microenvironments. Our laboratory uses molecular dynamics (MD) simulations with the recently developed Drude polarizable force field to investigate the conformational ensembles of model peptides and proteins, nucleic acids, and lipid membranes. In this application, we propose a research program that breaks new ground in exploring (1) the forces driving the unfolding of amyloidogenic peptides with and without post-translational modifications, (2) the effects of ions and noncanonical interactions in stabilizing DNA G-quadruplexes (GQ), and (3) the role of induced electronic polarization on small-molecule partitioning and peptide folding in phospholipid membranes. The unifying theme of these projects is an examination of the atomistic details driving conformational change with specific emphasis on the role of induced electronic polarization. During the project period, we propose to investigate conformational ensembles of several amyloidogenic peptides to understand the role of induced electronic polarization on peptide-peptide and peptide- water interactions (hydrogen bonding, electrostatic clashes, and other induced dipole-dipole interactions). Similarly, we will investigate DNA GQ with different folds (parallel, antiparallel, and mixed) to characterize how their nucleobase properties (alignment, dipole moments, etc.) and loop conformational ensembles are impacted by different monovalent ions and noncanonical base-base and base-phosphate interactions that stabilize GQ. The final project comprises simulations of peptides and small molecules in lipid membranes to understand partitioning, thermodynamics, and the strength of hydrogen bonds and other intrapeptide and intermolecular interactions in the hydrophobic core of the membrane, as these interactions are tied to the polarity of the surrounding medium. The specific goals for the five-year project period are to (1) determine interactions among amino acids in amyloidogenic peptides that dictate conformational change, (2) characterize the relative contributions of ions, water, and noncanonical base interactions in stabilizing DNA GQ, and (3) quantify the free energy changes associated with peptide folding and small-molecule partitioning in membranes. These projects are representative of the overall vision of the research program, to apply rigorous theoretical methods to complex biomolecules to understand the molecular basis for a variety of diseases (including neurodegenerative disorders and several types of cancer) and to use the resulting information to carry out computer-aided drug design against new biomolecular targets with the most advanced simulation models currently available.