Assessing the Strength of Weak Ties for Interpreting Human Exome

评估弱关系的强度以解释人类外显子组

• 批准号: 9813185
• 负责人: Suvobrata Chakravarty
• 金额: $ 41.69万
• 依托单位: SOUTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813185
• 关键词: Address; Algorithms; Amino Acid Sequence; Animal Model; Anions; Automobile Driving; Behavior; Biochemical; Biology; Cataloging; Catalogs; Chemistry; Collection; Databases; Detection; Dimensions; Environment; Exposure to; Foundations; G-Protein-Coupled Receptors; Genetic; Genetic Variation; Genome; Genomics; Genotype; Goals; Health; Human; Human Genetics; Human Genome; Hydrogen Bonding; Individual; Institution; Interdisciplinary Study; Investigation; Knowledge; Link; Maps; Measures; Mission; Modeling; Molecular; Molecular Genetics; Molecular Probes; Molecular Structure; Mutation; Nature; Organism; Outcome; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Proteins; Proteome; Public Health; Research; Research Methodology; Resolution; Resources; Role; Sodium Chloride; Structural Protein; Structure; Therapeutic; Training; United States National Institutes of Health; Variant; Yeasts; base; career; exome; experimental study; gene therapy; genetic variant; genome editing; innovation; insight; macromolecule; meetings; prevent; protein folding; protein function; protein protein interaction; protein structure; response; simulation; structural biology; three dimensional structure; undergraduate student; van der Waals force

A major challenge in genetics is to identify genetic variants driving phenotypic variation, and the analysis of natural variation in human protein sequences is an important avenue to meet the challenge. As weak noncovalent interactions play critical role in protein folding, assembly and recognition, structural analysis of how noncovalent interactions in human proteins, from one individual to another, vary will be critical. Our results suggest that thousands of noncovalent interactions, particularly weak ones (e.g., p-interactions, anion-quadrupole (AQ), hydrogen bonds etc.), are perturbed in human proteins due to natural variation. Like other p-interactions, AQ also plays important role in macromolecular structure. However, the strength of weak interactions (e.g., AQ) remain poorly understood, and therefore, the interpretation of the consequences of natural variation of human protein sequences remain incomprehensible. The absence of the knowledge of weak-interaction energetics and the comprehensive map of all weak interactions altered in human proteins will continue to significantly contribute to the lack of understanding of the origin of phenotypic variation. Continued existence of this knowledge gap represents an important problem because, until it is filled, how genetic variants drive phenotypic variation remain incomprehensible for beneficial genetic interventions. Our long-term goal is to better understand the role of weak noncovalent interactions in regulating protein function. The objective for this particular R15 application is to comprehensively measure the strength of a weak interaction (e.g., AQ) and to create a comprehensive catalogue of all noncovalent interaction in human protein structures that are altered due to natural human sequence variation. Our rationale is that (a) determination of the energy of a weak interaction (e.g., AQ) is likely to provide new insights by enabling subsequent studies on protein function by manipulating AQ; (b) the availability of a complete catalogue of fine structural details of natural missense variants of all human proteins will facilitate probing molecular mechanism of genetic variants driving phenotypic variation. The two specific aims are: 1) Determine the strength of AQ experimentally; 2) Create a database of 3D structural maps of natural missense variants of human proteins. For Aim-1, using 18 carefully chosen protein-peptide interfaces, we experimentally measure the strength of AQ that occur in various structural contexts for a comprehensive estimate. For Aim-2, using human exome aggregation consortium (ExAC) database, we provide a comprehensive, fine structural map of all noncovalent interactions in human protein structures that are perturbed due to natural variation. Using molecular dynamic simulations, we also probe the consequences of ExAC mutations in two functionally important human proteins. The approach is innovative for capturing a link between genetic and phenotypic variations at atomic resolution. The research is significant, because it is expected to vertically expand the understanding of how genetic variations contribute to phenotypic variation. That will enable preventative, therapeutic manipulations of human proteome.

遗传学的主要挑战是鉴定遗传变异驱动表型变异，并分析 人类蛋白质序列的自然变化是应对挑战的重要途径。如弱 非共价相互作用在蛋白质折叠，组装和识别，结构分析中起关键作用 从一个个体到另一个人的人类蛋白质中的非共价相互作用将是至关重要的。我们的结果 表明成千上万的非共价相互作用，尤其是弱相互作用（例如，P交互， 由于自然变异，在人蛋白中扰动了阴离子 - 四极杆（aq），氢键等）。喜欢 其他P交互，AQ在大分子结构中也起着重要作用。但是，弱的力量 相互作用（例如AQ）仍然很少理解，因此，解释了对后果的解释 人蛋白序列的自然变化仍然难以理解。缺乏知识 虚弱的互动能量和人类蛋白质中所有弱相互作用的综合图都将 继续显着有助于缺乏对表型变异起源的理解。持续 这种知识差距的存在代表了一个重要的问题，因为直到填充它， 变体驱动表型变异对于有益的遗传干预仍然难以理解。我们的长期 目标是更好地了解弱非共价相互作用在调节蛋白质功能中的作用。这 此特定R15应用的目的是全面衡量弱相互作用的强度 （例如AQ），并创建人类蛋白质结构中所有非共价相互作用的综合目录 由于自然的人类序列变化而改变的。我们的理由是（a）确定能量 弱相互作用（例如AQ）可能通过实现随后的蛋白质研究来提供新的见解 通过操纵AQ的功能； （b）完整的自然结构细节的完整目录 所有人类蛋白质的错义变体将促进探索遗传变异的分子机制 表型变异。两个具体目的是：1）通过实验确定AQ的强度； 2）创建一个 人类蛋白质自然错义变体的3D结构图的数据库。对于AIM-1，请仔细使用18 选择的蛋白质肽界面，我们通过实验测量了在各种AQ的强度 综合估计的结构背景。对于AIM-2，使用人类外显着聚集财团 （EXAC）数据库，我们提供了人类所有非共价相互作用的全面，精细的结构图 由于自然变异而受到干扰的蛋白质结构。使用分子动态模拟，我们也 探测两个在功能上重要的人蛋白中的EXAC突变的后果。方法是 在原子分辨率下捕获遗传和表型变异之间的联系的创新性。研究是 重要的是，因为期望它垂直扩展对遗传变异的理解 表型变异。这将使人类蛋白质组的预防性，治疗性操纵。