Insights into the Fold Organization of TIM Barrel from Interaction Energy Based Structure Networks

Abstract

There are many well-known examples of proteins with low sequence similarity, adopting the same structural fold. This aspect of sequence-structure relationship has been extensively studied both experimentally and theoretically, however with limited success. Most of the studies consider remote homology or “sequence conservation” as the basis for their understanding. Recently “interaction energy” based network formalism (Protein Energy Networks (PENs)) was developed to understand the determinants of protein structures. In this paper we have used these PENs to investigate the common non-covalent interactions and their collective features which stabilize the TIM barrel fold. We have also developed a method of aligning PENs in order to understand the spatial conservation of interactions in the fold. We have identified key common interactions responsible for the conservation of the TIM fold, despite high sequence dissimilarity. For instance, the central beta barrel of the TIM fold is stabilized by long-range high energy electrostatic interactions and low-energy contiguous vdW interactions in certain families. The other interfaces like the helix-sheet or the helix-helix seem to be devoid of any high energy conserved interactions. Conserved interactions in the loop regions around the catalytic site of the TIM fold have also been identified, pointing out their significance in both structural and functional evolution. Based on these investigations, we have developed a novel network based phylogenetic analysis for remote homologues, which can perform better than sequence based phylogeny. Such an analysis is more meaningful from both structural and functional evolutionary perspective. We believe that the information obtained through the “interaction conservation” viewpoint and the subsequently developed method of structure network alignment, can shed new light in the fields of fold organization and de novo computational protein design.

Structural Basis of the Novel S. pneumoniae Virulence Factor, GHIP, a Glycosyl Hydrolase 25 Participating in Host-Cell Invasion

“…As previously mentioned, GHIP contains a negatively charged groove located at the mouth of its TIM barrel, which is similar to the known TIM enzymes like triosphosphate isomerase and pyruvate kinase (Figure 1C) [46], [47]. Porter et al proposed that the catalytic machinery comprised four acidic residues equivalent to the Asp6, Asp90, Glu92, and Asp171 in PlyB, which are strictly conserved in the GH25 family [19].…”

Interaction Signatures Stabilizing the NAD(P)-Binding Rossmann Fold: A Structure Network Approach

“…Thus a judicious use of network theory and deft manipulation of the adjacency matrices representing the interactions in protein structure networks can provide detail insights into the structural constraints that favor formation of a common fold. A slightly modified version of this methodology in which the interactions are specified in terms of energy, has also been successfully applied recently to identify the family-specific features in the context of the TIM barrel fold [34]. This methodology can be further extended across different superfamilies, with higher sequence diversity and different functions but sharing a common fold.…”

In silico mutational studies of Hsp70 disclose sites with distinct functional attributes

“…The network approach has enabled the study of specific proteins and has helped reveal interesting features not directly evident from the structure or sequence homology . For example, interaction conservation was utilized in phylogenetic analysis of remote homologs of the TIM barrel fold to reveal loop‐based conserved interactions near the active site . In our current view, the network of interactions in a protein is composed of a set of contacts designated by the spatial arrangement in three‐dimensional space, resulting in a small world network with Poisson distribution of the number of neighbors (also termed degree), allocating necessary contact information for proper functioning under a plethora of external perturbations …”