Characterizing the relation of functional and Early Folding Residues in protein structures using the example of aminoacyl-tRNA synthetases [article]

Sebastian Bittrich, Michael Schroeder, Dirk Labudde
2018 bioRxiv   pre-print
Proteins are chains of amino acids which adopt a three-dimensional structure and are then able to catalyze chemical reactions or propagate signals in organisms. Without external influence, most proteins fold into their correct structure, and a small number of Early Folding Residues (EFR) have previously been shown to initiate the formation of secondary structure elements and guide their respective assembly. A dataset of 30 proteins and 3,337 residues provided by the Start2Fold database was
more » ... zed. Proteins were represented as residue graphs in order to analyze topological descriptors of EFR. These residues constitute crucial connectors of protein regions which are distant at sequence level. Especially, these residues exhibit a high number of non-covalent residue-residue contacts such as hydrogen bonds and hydrophobic interactions. This tendency also manifests as energetically stable local regions in a knowledge-based potential. These distinct characteristics can give insights into what drives certain residues to initiate and guide the folding process. Furthermore, these features are not only characteristic for EFR but also differ significantly with respect to functional residues such as active or ligand binding sites. This unveils a split between structurally and functionally relevant residues in proteins which can improve their evolvability and robustness. Aminoacyl-tRNA synthetases demonstrate this separation in an evolutionary context: the positions of EFR are preserved over the course of evolution and evolutionary pressure is smaller in comparison to positions relevant for protein function. The shown separation between functional and EFR has implications for the prediction of mutation effects as well as protein design and can provide insights into the evolution of proteins.
doi:10.1101/290627 fatcat:hhlbabvnkvhyfpnjooln4ynyta