Abstract
The conservation of the intrinsic dynamics of proteins emerges as we attempt to understand the relationship between sequence, structure and functional conservation. We characterise the conservation of such dynamics in a case where the structure is conserved but function differs greatly. The triosephosphate isomerase barrel fold (TBF), renowned for its 8 β-strand-α-helix repeats that close to form a barrel, is one of the most diverse and abundant folds found in known protein structures. Proteins with this fold have diverse enzymatic functions spanning five of six Enzyme Commission classes, and we have picked five different superfamily candidates for our analysis using elastic network models. We find that the overall shape is a large determinant in the similarity of the intrinsic dynamics, regardless of function. In particular, the β-barrel core is highly rigid, while the α-helices that flank the β-strands have greater relative mobility, allowing for the many possibilities for placement of catalytic residues. We find that these elements correlate with each other via the loops that link them, as opposed to being directly correlated. We are also able to analyse the types of motions encoded by the normal mode vectors of the α-helices. We suggest that the global conservation of the intrinsic dynamics in the TBF contributes greatly to its success as an enzymatic scaffold both through evolution and enzyme design.
Highlights
Understanding a proteins’ inherent flexibility, or intrinsic dynamics, is fundamental to understanding the mechanism with which they are able to perform their function
We saw that this fold is successful in providing rigid positions for all catalytic residues, and that most other residue positions involved in function share this property
We believe that the number of rigid positions offered by the triosephosphate isomerase barrel fold (TBF) combined to the possibility of adding neighbouring loops or other accessory elements is key to explaining its versatility
Summary
Understanding a proteins’ inherent flexibility, or intrinsic dynamics, is fundamental to understanding the mechanism with which they are able to perform their function. We know little about the conservation of dynamic properties in a structural fold, whether the similarity is due to or regardless of evolutionary conservation. Protein families can be distinguished by their similarity in dynamics [1, 2], there is growing evidence that this may be influenced by the level of similarity in their overall structural topology, which can be robust to mutations [3, 4]. General properties have been ascribed to elements of protein structures, such as the correlated motions of β-sheets [5], while a clear similarity between the flexibilities of non-homologous enzymes catalysing the same reaction has been demonstrated [6]. Studies by Micheletti and colleagues have suggested that dynamics is conserved for function, regardless of the structural conservation [8, 9]
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