A perturbative view of protein structural variation

JULIÁN ECHAVE; F. M. FERNÁNDEZ

PROTEINS: STRUCTURE, FUNCTION AND GENETICS

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2010 vol. 78 p. 173 - 180

0887-3585

It was recently found that the lowest-energy collective normal modes dominate the evolutionarydivergence of protein structures. This was attributed to a presumed functional importance ofsuch motions, i.e., to natural selection. In contrast to this selectionist explanation, we proposedthat the observed behavior could be just the expected physical response of proteins torandom mutations. This proposal was based on the success of a linearly forced elastic networkmodel (LFENM) of mutational effects on structure to account for the observed pattern ofstructural divergence. Here, to further test the mutational explanation and the LFENM, we analyzethe structural differences observed not only in homologous (globin-like) proteins but also inunselected experimentally engineered myoglobin mutants and in wild-type variants subject toother perturbations such as ligand-binding and pH changes. We show that the lowest normalmodes dominate structural change in all the cases considered and that the LFENM reproducesthis behavior quantitatively. The collective nature of the lowest normal modes results in global conformational changes that depend little on the exact nature or location of the perturbation.Significantly, the evolutionarily conserved structural core matches the regions observed to be more robust with respect to mutations, so that the core would be more conserved even under unselected random mutations. In a word, the observed patterns of structural variation can be seen as the natural response of proteins to perturbations and can be adequately modeled using the LFENM, which serves as a common framework to relate a priori different phenomena.