Counterbalance of ligand‐ and self‐coupled motions characterizes multispecificity of ubiquitin

Date hub proteins are a type of proteins that show multispecificity in a time‐dependent manner. To understand dynamic aspects of such multispecificity we studied Ubiquitin as a typical example of a date hub protein. Here we analyzed 9 biologically relevant Ubiquitin‐protein (ligand) heterodimer structures by using normal mode analysis based on an elastic network model. Our result showed that the self‐coupled motion of Ubiquitin in the complex, rather than its ligand‐coupled motion, is similar to the motion of Ubiquitin in the unbound condition. The ligand‐coupled motions are correlated to the conformational change between the unbound and bound conditions of Ubiquitin. Moreover, ligand‐coupled motions favor the formation of the bound states, due to its in‐phase movements of the contacting atoms at the interface. The self‐coupled motions at the interface indicated loss of conformational entropy due to binding. Therefore, such motions disfavor the formation of the bound state. We observed that the ligand‐coupled motions are embedded in the motions of unbound Ubiquitin. In conclusion, multispecificity of Ubiquitin can be characterized by an intricate balance of the ligand‐ and self‐coupled motions, both of which are embedded in the motions of the unbound form.