Experimentally derived quantitative model of protein evolution

实验得出的蛋白质进化定量模型

• 批准号: RGPIN-2016-06566
• 负责人: Serohijos, Adrian
• 金额: $ 2.62万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710320
• 关键词: Experimentally; derived; quantitative; model; protein

Phylogenetic analysis of sequences is an essential computational tool in biology. It is central to understanding the evolution of protein structure and function, speciation, the relationship among genes and genealogies, and the dynamics of the spread of pathogens. In biochemistry, it is the starting point for understanding the evolution of structure-function relationship in proteins. At the core of any phylogenetics method is a quantitative model of molecular evolution that describes the rate of mutation and the stringency of selection. However, a major challenge is that the widely used quantitative models of coding sequence evolution assume that all sites in a gene (or protein) are independent and equivalent. Both assumptions are inconsistent with protein biophysics. Additionally, this transition matrix is applied to all proteins, ignoring the fact that protein folds affect the stringency of selection in the substitution matrix.The long-term objective of the research program is to address these challenges by developing novel methods in molecular phylogenetics. A major innovative component is that instead of assuming a substitution matrix or estimating them from sequence alignments, we will directly measure the amino acid propensity for each site in the protein and embed it in a phylogenetics model. In the near term, we will focus our methods development on dihydropteroate synthase (DHPS), a core metabolic enzyme in the folate synthesis pathway. DHPS is an excellent model because it is an important target of sulfonamide antibiotics and follows a TIM-barrel fold, the most prevalent type of protein fold in a proteome. First, we will determine the fitness landscape of DHSP by performing high-throughput measurement of the per site amino acid preference. Second, we will develop a phylogenetic inference model based on the experimentally derived substitution matrix. Third, we will reconstruct the evolution of DHPS structure-function relationship using the new phylogenetic inference model. While we focus on DHPS on the short-term, the long-term view of our research program is to generalize this approach to other protein folds. Indeed, this approach could lead to a proteome-wide experimentally derived model of evolution. This multi-disciplinary research program will be used to train students and other highly qualified personnel at the interface of biophysics, biochemistry, molecular evolution, and bioinformatics. This training broad training in both theory and experiment could also provide valuable training for students for their future careers in both academia and industry.

序列的系统发育分析是生物学中一种重要的计算工具。它对于理解蛋白质结构和功能的进化、物种形成、基因和谱系之间的关系以及病原体传播的动力学至关重要。在生物化学中，它是理解蛋白质结构-功能关系进化的起点。任何遗传学方法的核心都是一个分子进化的定量模型，它描述了突变的速率和选择的严格性。然而，一个主要的挑战是，广泛使用的编码序列进化的定量模型假设基因（或蛋白质）中的所有位点是独立和等效的。这两种假设都与蛋白质生物物理学不一致。此外，该转换矩阵适用于所有蛋白质，忽略了蛋白质折叠影响置换矩阵中选择的严格性的事实。该研究计划的长期目标是通过开发分子遗传学的新方法来解决这些挑战。一个主要的创新部分是，我们将直接测量蛋白质中每个位点的氨基酸倾向性，并将其嵌入遗传学模型中，而不是假设取代矩阵或从序列比对中估计它们。 在短期内，我们将把我们的方法发展的重点放在二氢蝶酸合酶（DHPS），在叶酸合成途径的核心代谢酶。DHPS是一个很好的模型，因为它是磺胺类抗生素的一个重要靶标，并且遵循TIM桶折叠，这是蛋白质组中最常见的蛋白质折叠类型。首先，我们将通过对每个位点的氨基酸偏好进行高通量测量来确定DHSP的适应度景观。其次，我们将开发一个系统发育推理模型的基础上，实验推导出的替代矩阵。第三，我们将重建DHPS结构功能关系的进化，使用新的系统发育推理模型。虽然我们在短期内专注于DHPS，但我们研究计划的长期观点是将这种方法推广到其他蛋白质折叠。事实上，这种方法可能会导致蛋白质组范围内的实验衍生的进化模型。 这个多学科的研究计划将用于培养学生和其他高素质的人才在生物物理学，生物化学，分子进化和生物信息学的接口。这种在理论和实验方面的广泛培训也可以为学生未来在学术界和工业界的职业生涯提供有价值的培训。