Modeling Complex between FBA and TIM: Functional Motions of FBA and TIM are Preserved in their Complex

Abstract

Fructuose bisphostate aldolase (FBA) and triosephosphate isomerase (TIM) are the fourth and fifth enzymes in the glycolysis pathway and they are known to bind. FBA cleaves the six-carbon fructose 1, 6-bisphosphate into two three-carbon components – dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (GAP). TIM converts DHAP into GAP, a substrate for the subsequent synthetic step. These two alpha/beta barrel proteins have high structural similarity – with a core RMSD 4.8A. These two enzymes have low activity in the monomeric form with the functionally active structures present in higher oligomeric states. By applying Elastic Network Model, we find the modes of motions that are functionally important for these proteins. We build models for the complex between these two proteins to investigate their important motions in their complexes as well as for their different oligomeric states including those that are different in different species to learn their important modes of motions for different functionalities. For each protein, by multiple sequence alignment across the species, we predict the coevolving residues and cluster these residues along the structure. We build the information transfer pathways from the important interface residues to the catalytic residues. Change in these pathways in different oligomeric states maybe be related to the change of motions in the catalytic region in different oligomeric states. We use this knowledge about the changes in motions and the information transfer pathways within the structure of these interacting proteins as constraints for selecting the computational docked models of complexes between these two proteins to preserve their functional motions.