Elucidating the dynamical and structural molecular factors at the origin of non-enzymatic protein-protein and protein-DNA cross-links

阐明非酶蛋白质-蛋白质和蛋白质-DNA 交联起源的动力学和结构分子因素

• 批准号: 10709399
• 负责人: Valerie Vaissier Welborn
• 金额: $ 38.18万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709399
• 关键词: Address; Adsorption; Aging; Alzheimer' s Disease; Amines; Biological; Bone Diseases; Carbohydrates; Cardiovascular Diseases; Chronic Kidney Failure; Collagen; Computing Methodologies; DNA; DNA-protein crosslink; Data; Dehydration; Development; Diabetes Mellitus; Disease; Elastin; Environment; Foundations; Genetic Complementation Test; Glucose; Goals; Hydration status; Intervention; Knowledge; Length; Location; Mediating; Metastatic Neoplasm to the Bone; Microscopic; Mission; Modeling; Molecular; National Institute of General Medical Sciences; Nature; Neoplasm Metastasis; Parkinson Disease; Pathologic; Pathology; Post-Translational Protein Processing; Prevention; Process; Proteins; Protocols documentation; Proxy; Reaction; Research; Retinal Diseases; Side; Site; Source Code; System; Therapeutic; Time; Tissues; Water; adduct; alpha synuclein; crosslink; density; electric field; experimental study; glycation; kinetic model; macromolecule; mineralization; molecular dynamics; nucleobase; open source; quantum; skin disorder; sugar; theories; therapeutic development

Project Summary Non-enzymatic protein-protein and protein-DNA cross-links are deleterious post-translational modifications that have been associated with many severe pathologies, including cancer metasta- sis, retinopathy, chronic renal failure, skin and bone disorders, aging, diabetes, Alzheimer’s, Par- kinson’s and cardiovascular diseases. However, the development of therapeutic strategies is hin- dered by our poor understanding of their formation. We propose to address this gap in knowledge using computational methods based on intrinsic electric field calculations. Our goal is to identify the structural and dynamical molecular factors at the origin of the formation of non-enzymatic protein-protein and protein-DNA cross-links. We focus our study on sugar-mediated cross-links, initiated by glycation reactions, as it has been shown to occur in a broad range of systems. We hypothesize that partial depletion of the protein (or DNA) hydration layer exposes side chains (or nucleobases) to surrounding carbohydrates. This facilitates glycation reactions whereby reducing sugars (glucose) react with the free amine groups. Glycated proteins and DNA then have enhanced ability to form adducts, altering their biofunction. Our proposed research seeks to provide a molecular interpretation of sugar-mediated cross-link formation and can be divided into three thrusts ; each of which with the potential to expand into a standalone research direction. First, we propose to characterize the density of the hydration layer of healthy and pathological proteins and DNA strands known to aggregate (collagen, elastin and α-synuclein) at the quan- tum level. Our preliminary data on mineralized collagen systems show that water adsorption is controlled by the nature of the environment rather than the nature of the adsorption site, consistent with experimental observations. This suggests that the density functional theory protocol we de- veloped for this study is suitable for the characterization of macromolecule-water interactions. Second, we propose to model carbohydrate reactivity in dehydrated and hydrated biomole- cules, as a proxy for non-enzymatic glycation reactions. The novelty of our approach is to intro- duce accurate reactivity information in classical molecular dynamics simulations using intrinsic electric fields as a metric for bond formation. Our preliminary data verify the feasibility of such study and include the development of an open-source code that allows this type of calculations. Finally, we propose to integrate our atomistic data into a microscopic kinetic model of protein- protein and protein-DNA cross-linking processes. With this model, we aim to predict the critical density, location, cooperativity and strength of cross-links that are associated with known patho- logies, paving the way towards the identification of therapeutic points of intervention.

项目概要 非酶促蛋白质-蛋白质和蛋白质-DNA 交联在翻译后是有害的 与许多严重病理学相关的修饰，包括癌症转移 sis、视网膜病变、慢性肾功能衰竭、皮肤和骨骼疾病、衰老、糖尿病、阿尔茨海默氏症、Par- 然而，治疗策略的发展却令人欣喜。 由于我们对它们的形成缺乏了解，我们建议解决这一知识差距。 使用基于固有电场计算的计算方法我们的目标是识别。 非酶促物质形成起源的结构和动力学分子因素 我们的研究重点是糖介导的交联， 由糖化反应引发，因为它已被证明发生在广泛的系统中。 我们追求蛋白质（或DNA）水化层的部分耗尽暴露侧面 链（或核碱基）到周围的碳水化合物，因此促进糖化反应。 然后还原糖（葡萄糖）与游离胺基团和 DNA 发生反应。 增强形成加合物的能力，改变其生物功能。 提供糖介导的交联形成的分子解释，并可分为 分为三个主旨；每个主旨都有可能扩展到一个独立的研究方向。 首先，我们建议表征健康和病理的水化层的密度 已知在量子点聚集的蛋白质和 DNA 链（胶原蛋白、弹性蛋白和 α-突触核蛋白） 我们关于矿化胶原蛋白系统的初步数据表明，水的吸收是 受环境性质而非吸附位点性质控制，一致 通过实验观察，这表明我们设计了密度泛函理论协议。 本研究开发的适用于大分子-水相互作用的表征。 其次，我们建议模拟脱水和水合生物分子中的碳水化合物反应性 cules，作为非酶糖化反应的代表，我们方法的新颖之处在于引入了 使用内在的经典分子动力学模拟得出准确的反应信息 我们的初步数据验证了这种方法的可行性。 研究并开发允许此类计算的开源代码。 最后，我们建议将我们的原子数据整合到蛋白质的微观动力学模型中 通过这个模型，我们的目标是预测关键的蛋白质和蛋白质-DNA 交联过程。 与已知病理相关的交联的密度、位置、协同性和强度 学，为确定干预治疗点铺平道路。