Bioinformatics Institute, Agency for Science, Technology and Research, Singapore, Singapore.
PLoS One. 2011;6(9):e24382. doi: 10.1371/journal.pone.0024382. Epub 2011 Sep 12.
In this work, belonging to the field of comparative analysis of protein sequences, we focus on detection of functional specialization on the residue level. As the input, we take a set of sequences divided into groups of orthologues, each group known to be responsible for a different function. This provides two independent pieces of information: within group conservation and overlap in amino acid type across groups. We build our discussion around the set of scoring functions that keep the two separated and the source of the signal easy to trace back to its source.We propose a heuristic description of functional divergence that includes residue type exchangeability, both in the conservation and in the overlap measure, and does not make any assumptions on the rate of evolution in the groups other than the one under consideration. Residue types acceptable at a certain position within an orthologous group are described as a distribution which evolves in time, starting from a single ancestral type, and is subject to constraints that can be inferred only indirectly. To estimate the strength of the constraints, we compare the observed degrees of conservation and overlap with those expected in the hypothetical case of a freely evolving distribution.Our description matches the experiment well, but we also conclude that any attempt to capture the evolutionary behavior of specificity determining residues in terms of a scalar function will be tentative, because no single model can cover the variety of evolutionary behavior such residues exhibit. Especially, models expecting the same type of evolutionary behavior across functionally divergent groups tend to miss a portion of information otherwise retrievable by the conservation and overlap measures they use.
在这项属于蛋白质序列比较分析领域的工作中，我们专注于检测残基水平上的功能特化。作为输入，我们采用了一组分为同源物组的序列，每组序列都已知负责不同的功能。这提供了两条独立的信息：组内保守性和组间氨基酸类型的重叠。我们围绕着将这两个信息分离开来的评分函数集展开讨论，并且信号的来源很容易追溯到其来源。我们提出了一种功能分歧的启发式描述，包括残基类型的可交换性，无论是在保守性还是重叠度量中，并且除了正在考虑的组之外，不会对其他组的进化率做出任何假设。在同源物组内某个位置可接受的残基类型被描述为从单个祖先类型开始随时间演变的分布，并且受到只能间接推断的约束。为了估计约束的强度，我们将观察到的保守性和重叠程度与在自由进化分布的假设情况下预期的程度进行比较。我们的描述与实验吻合得很好，但我们也得出结论，任何试图用标量函数来捕捉特异性决定残基的进化行为的尝试都将是试探性的，因为没有单一的模型可以涵盖这些残基所表现出的各种进化行为。特别是，期望在功能上不同的组中表现出相同类型的进化行为的模型往往会错过通过它们使用的保守性和重叠度量可以获得的一部分信息。
