Coevolution of function and the folding landscape: correlation with density of native contacts

Abstract

The relationship between the folding landscape and function of evolved proteins is explored by comparison of the folding mechanisms for members of the flavodoxin fold. CheY, Spo0F, and NtrC have unrelated functions and low sequence homology but share an identical topology. Recent coarse-grained simulations show that their folding landscapes are uniquely tuned to properly suit their respective biological functions. Enhanced packing in Spo0F and its limited conformational dynamics compared to CheY or NtrC lead to frustration in its folding landscape. Simulation as well as experimental results correlate with the local density of native contacts for these and a sample of other proteins. In particular, protein regions of low contact density are observed to become structured late in folding; concomitantly, these dynamic regions are often involved in binding or conformational rearrangements of functional importance. These observations help to explain the widespread success of Gō-like coarse-grained models in reproducing protein dynamics.

FIGURE 1

N-terminal (yellow), C-terminal (blue) and, where applicable, central (magenta) subdomains for CheY (A), cutinase (B), flavodoxin (C), protein L/G (D), T4L (E), IL-1β (F), and HP35 (G). Active site residues are shown in green.

FIGURE 2

Subdomain folding order can be predicted from large (dark shaded) ratios of contact density and chain compaction (see text for definitions). Ratios <1.0 denote incorrect predictions. For small proteins (×), one or both predictors approach unity.