Proteins with greater influence on network dynamics evolve more slowly but are not more essential

TL;DR

This study introduces dynamical influence as a detailed measure of protein importance in biochemical networks, revealing that proteins with higher influence evolve more slowly, independently of their essentiality or expression characteristics.

Contribution

The paper develops a new measure called dynamical influence based on biochemical models, linking it to evolutionary rates and challenging previous assumptions about essentiality.

Findings

Proteins with higher dynamical influence evolve more slowly.

Dynamical influence is not correlated with protein essentiality.

Influence on evolution rate is independent of expression and gene features.

Abstract

A fundamental question for evolutionary biology is why rates of evolution vary dramatically between proteins. Perhaps surprisingly, it is controversial how much a protein's functional importance affects its rate of evolution. In most studies, functional importance has been measured on the coarse scale of protein knock-outs, while evolutionary rate has been measured on the fine scale of amino acid substitutions. Here we introduce dynamical influence, a finer measure of protein functional importance. To measure dynamical influence, we first use detailed biochemical models of particular reaction networks to measure the influence of each reaction rate constant on network dynamics. We then define the dynamical influence of a protein to be the average influence of the rate constants for all reactions it is involved in. Using models of a dozen biochemical systems and sequence data from vertebrates, we show that dynamical influence and evolutionary rate are negatively correlated; proteins with greater dynamical influence evolve more slowly. We also show that proteins with greater dynamical influence are not more likely to be essential. This suggests that there are many cellular reactions whose presence is essential for life, but whose quantitative rate is relatively unimportant to fitness. We also provide evidence that the effect of dynamical influence on evolutionary rate is independent of protein expression level, expression specificity, gene compactness, and reaction degree. Dynamical influence offers a finer view of functional importance, and our results suggest that focusing on essentiality may have previously led to an underestimation of the role function plays in protein evolution.