Examining the Flexibility of Tim Barrel Proteins Based on their Structural Topology

Abstract

The eight-fold beta/alpha barrel-like fold, first seen in triose-phosphate isomerase (TIM), is a common and versatile fold for proteins. Proteins in this classification have diverse enzymatic functions spanning five of six Enzyme Commission classes. Studies have characterized the sequence, structure, localized dynamics and electrostatics of TIM proteins, but the flexibility of the fold is understudied. We use coarse-grained and all-atom normal modes analysis to look at the principle TIM beta/alpha barrel secondary structure elements of five structures from distinct families with low sequence similarity between 23 and 38.5 % and low structure similarity. We report that the eight core beta strands behave independently of the eight flanking alpha helices. The strands and helices repeat in tandem at the sequence level, yet the strands form a core that moves minimally while the helices display greater relative mobility in all of the structures. This core formed by the beta-strands is rigid in all the structures. This is despite the varying loop lengths between them and the presence of accessory secondary structures in some cases. We found that the atomic fluctuations of each of the beta-strands have a high correlation with its immediate beta-strand neighbour in the core. Compared to the beta strands, the alpha helices have less correlation with each other and almost none with the strands. We also defined rotation and translation vectors to decompose the type of movements to which the normal modes of these TIMs correspond. We relate differences in the mobility of the individual secondary structure elements to the differences in function and structure of the five different enzymes.