Inferring physico-chemical constraints at individual sites in protein evolution

推断蛋白质进化中各个位点的物理化学限制

基本信息

批准号：
9107818
负责人：
Joel Okrent Wertheim
金额：
$ 22.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107818
关键词：
Accounting Address Affect Amino Acid Sequence Amino Acids Biochemical Biological Blood Cerebrospinal Fluid Chemicals Code Collaborations Collection Computer Simulation Computing Methodologies Data Data Set Detection Evolution Funding Genes Genomics Health Human Immune Immune response Individual Intuition Methodology Methods Modeling Mutation Natural Selections Peptide Sequence Determination Phylogenetic Analysis Phylogeny Prevention Property Proteins Publishing Recording of previous events Sequence Alignment Sequence Analysis Site Statistical Models Testing Time Trees United States National Institutes of Health Vaccine Design Viral Viral Genome Virus base chemical property drug development experience hydropathy improved insight interest pathogen pressure protein folding receptor function reproductive tract sample fixation structural biology viral transmission

项目摘要

DESCRIPTION (provided by applicant): It is often important to detect sites where mutations have been driven to fixation by positive selection, or which are constrained by purifying selection. Underlying such selective pressures are the physico-chemical differences (e.g. in hydropathy, polarity or volume) between different amino acids. Even when some amino acid changes at a site are favored by positive selection (e.g. because substituting an amino acid with different polarity may be favorable), selective constraints can still be expected to suppress other changes at the same site (e.g. because an amino acid with different volume would disrupt the folding of the protein). Thus different selective pressure can act on different properties at the same site. Moreover, a physico-chemical property that is important to conserve at one site may be unimportant at another. In this project we will use our expertise in computational and statistical modeling of evolution and selection to develop computational and statistical methodology to elucidate which physico-chemical properties are important at which sites. Our methods will identify not only functionally important sites experiencing selection, but the physico-chemical constraints under which evolution operates at those sites and the selective pressure causing some physico-chemical properties to change adaptively. We will use these methods to study the biochemical basis of adaptation in several biomedically important contexts, including immune escape and reversion in viral pathogens, viral transmission, and viral adaptation to different host compartments.

描述（由申请人提供）：检测位点通常很重要，其中突变被驱动以通过阳性选择固定，或者通过净化选择来限制。这种选择性压力的基础是不同氨基酸之间的物理化学差异（例如在水性质，极性或体积中）。即使在站点上的某些氨基酸变化受到阳性选择的青睐（例如，以不同极性代替氨基酸可能是有利的），仍然可以预期选择性约束可以抑制其他在同一部位发生变化（例如，由于具有不同体积的氨基酸会破坏蛋白质的折叠）。因此，不同的选择压力可以在同一站点的不同特性上作用。此外，在一个地点保存很重要的物理化学特性在另一个地点可能并不重要。在这个项目中，我们将在进化和选择的计算和统计模型中使用我们的专业知识来开发计算和统计方法，以阐明哪些物理化学特性在哪些站点上很重要。我们的方法不仅会确定具有选择选择的功能重要的站点，而且还将确定进化在这些站点上运行的物理化学约束以及导致某些物理化学特性自适应改变的选择性压力。我们将使用这些方法在几种生物医学重要的情况下研究适应的生化基础，包括免疫逃生和病毒病原体的回归，病毒传播以及对不同宿主室的病毒适应。