Exploring Electronic Polarization in Biomolecular Folding and Interactions

探索生物分子折叠和相互作用中的电子极化

基本信息

批准号：
10701042
负责人：
Justin Alan Lemkul
金额：
$ 22.85万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-06-30
项目状态：
已结题

项目摘要

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.

项目概要驱动水溶液中蛋白质和核酸以及脂质中蛋白质构象变化的力膜的特征仍然不完全。理论方法非常适合建立关系在结构和能量学之间，为确定生物潜在的力量提供关键信息不同细胞微环境中的过程。我们的实验室使用分子动力学 (MD) 模拟用最近开发的Drude极化力场来研究模型的构象系综肽和蛋白质、核酸和脂膜。在此申请中，我们提出了一个研究计划这在探索 (1) 驱动淀粉样肽展开的力量方面开辟了新天地没有翻译后修饰，(2) 离子和非规范相互作用对稳定 DNA 的影响 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的肽折叠。这些项目的统一主题是对驱动构象变化的原子细节，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系综淀粉样肽以了解诱导电子极化对肽-肽和肽-的作用水相互作用（氢键、静电碰撞和其他诱导的偶极子-偶极子相互作用）。同样，我们将研究具有不同折叠（平行、反平行和混合）的 DNA GQ，以表征如何它们的核碱基特性（排列、偶极矩等）和环构象集合受到影响通过不同的单价离子和非常规的碱基-碱基和碱基-磷酸盐相互作用来稳定 GQ。最终项目包括模拟脂膜中的肽和小分子，以了解分配、热力学以及氢键和其他肽内和分子间的强度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介质。五年项目期的具体目标是 (1) 确定淀粉样肽中决定构象变化的氨基酸，（2）表征相对离子、水和非规范碱基相互作用在稳定 DNA GQ 中的贡献，以及 (3) 量化游离与膜中肽折叠和小分子分配相关的能量变化。这些项目代表研究计划的总体愿景，将严格的理论方法应用于复杂的研究生物分子以了解多种疾病（包括神经退行性疾病）的分子基础和几种类型的癌症）并使用所得信息进行计算机辅助药物设计具有当前可用的最先进模拟模型的新生物分子靶标。