Analysis-Low-complexity Amino Acid-Nucleotide Sequences

该项目的目标是使用计算方法定义和分析显示组成偏差的蛋白质和核苷酸序列片段，并了解其结构，功能和进化意义及其病理学。这些序列包括局部低复杂性区域或结构域，包括构象移动或本质上非结构化的蛋白质区域，串联重复序列，以及更普遍分布的氨基酸含量偏倚。后者可以反映基因组水平上的定向突变压力和特定于蛋白质或结构域功能的限制。低复杂性区域包含大部分基因组编码的氨基酸，并且可能包含一些氨基酸的同聚束或马赛克，或者重复的模式，通常是微妙的，包括那些典型的非球状结构域。新的数学定义和算法已经被开发出来，用于识别成分偏倚区域，并发现和分析这些区域与其结构、相互作用、生物功能和进化相关的特性。由富含at或gc的基因组（包括几种重要传染病生物的基因组）编码的蛋白质显示出强烈的背景偏差：这给正在解决的序列比对算法带来了问题。在许多涉及细胞分化和胚胎发育、RNA加工、转录调控、信号转导以及细胞和细胞外结构完整性方面的蛋白质中，都存在低复杂性和串联重复的氨基酸序列的局部区域。实验数据表明，低复杂性的蛋白质片段通常是非球形的，本质上是非结构化的，或者构象移动的：然而，对这些结构域的分子结构和动力学的了解仍然非常有限。它们通常相对难以用晶体学和核磁共振来研究，并且它们占当前结构数据库中残基的不到1%。因此，数学上严格的序列分析和从头算量子化学方法，以及一些相关的高分辨率结构数据，是深入了解这些蛋白质区域和提出有待实验研究的问题的首选方法。这些方法对于核苷酸和氨基酸序列在序列数据库检索和比对分析中检测和消除一些伪影也很有价值。

The goal of this project is to define and analyze, using computational methods, segments of protein and nucleotide sequences showing compositional bias and to understand their structural, functional and evolutionary significance, and their pathology. These sequences include local low complexity regions or domains, including conformationally mobile or intrinsically unstructured regions of proteins, tandemly-repeated sequences, and also more generally distributed amino acid content bias. The latter can reflect directional mutation pressures at the genomic level and constraints specific to protein or domain function. Low complexity regions comprise a large proportion of the genome-encoded amino acids, and may contain homopolymeric tracts or mosaics of a few amino acids, or repeated patterns, frequently subtle, including those typical of many non-globular domains. New mathematical definitions and algorithms have been developed to identify regions of compositional bias, and to discover and analyze properties of these regions relevant to their structures, interactions, biological functions, and evolution. Strong background bias is shown by proteins encoded by very AT-rich or GC-rich genomes, which include those of several important infectious disease organisms: these raise problems for sequence alignment algorithms which are being addressed. Local regions of low complexity and tandemly repeated amino acid sequences occur in many proteins involved in cellular differentiation and embryonic development, RNA processing, transcriptional regulation, signal transduction and aspects of cellular and extracellular structural integrity. Experimental data indicate that low complexity segments of proteins are generally non-globular, intrinsically unstructured, or conformationally mobile: however, knowledge of the molecular structures and dynamics of these domains is still very limited. They are generally relatively intractable to investigation by crystallography and NMR, and they account for less than 1% of the residues in current structural databases. Hence, mathematically rigorous sequence analysis and ab initio quantum chemical methods, together with some relevant high-resolution structural data, are methods of choice for gaining insights into these regions of proteins and for raising questions to be investigated expermentally. These methods are also valuable, for both nucleotide and amino acid sequences, in detecting and eliminating some artifacts in sequence database searches and alignment analysis.