Determinants, Discriminants, Conserved Residues - A Heuristic Approach to Detection of Functional Divergence in Protein Families

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.

本研究隶属于蛋白质序列比较分析领域，聚焦于残基水平（residue level）上的功能特化检测。作为输入数据集，我们采用一组被划分为多个直系同源物（orthologues）组的序列，已知每个组负责执行不同的生物学功能。这一设置提供了两类独立的信息：组内保守性与不同组间氨基酸类型的重叠性。我们围绕一组评分函数（scoring functions）展开讨论，这类评分函数能够将两类信息区分开来，且便于将信号溯源至其原始来源。我们提出一种功能分化（functional divergence）的启发式描述，该描述在保守性度量与重叠性度量中均纳入了残基类型可交换性（residue type exchangeability），且除所研究的目标组外，不对其余组的进化速率作出任何假设。直系同源物组内特定位置可接受的残基类型被描述为一种随时间演化的分布，其起源于单一祖先残基类型（ancestral type），并受仅能间接推断的约束条件限制。为估算约束强度，我们将观测到的保守性与重叠性程度，与自由演化分布的假想场景下的预期值进行对比。我们的描述与实验结果契合度较高，但同时也指出，任何试图通过标量函数（scalar function）来刻画特异性决定残基（specificity determining residues）演化行为的尝试都将是试探性的，因为不存在单一模型能够涵盖这类残基所表现出的多样演化行为。尤其值得注意的是，假设功能分化组间具有统一演化行为的模型，往往会丢失一部分可通过其所使用的保守性与重叠性度量本可获取的信息。