A perturbative view of protein structural variation

Abstract

It was recently found that the lowest-energy collective normal modes dominate the evolutionary divergence of protein structures. This was attributed to a presumed functional importance of such motions, i.e., to natural selection. In contrast to this selectionist explanation, we proposed that the observed behavior could be just the expected physical response of proteins to random mutations. This proposal was based on the success of a linearly forced elastic network model (LFENM) of mutational effects on structure to account for the observed pattern of structural divergence. Here, to further test the mutational explanation and the LFENM, we analyze the structural differences observed not only in homologous (globin-like) proteins but also in unselected experimentally engineered myoglobin mutants and in wild-type variants subject to other perturbations such as ligand-binding and pH changes. We show that the lowest normal modes dominate structural change in all the cases considered and that the LFENM reproduces this 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.