From The Polymer Nature Of Proteins To The Evolution Of Protein Function

Abstract

We develop a new view on evolution of protein function which is based on the key role of a polymer nature of protein polypeptide chains in determining structure and evolution of proteins. Polypeptide backbone flexibility establishes a restriction on the size and shape of basic structural units of proteins. These elements, closed loops, are formed by the returns of the protein backbone and have a characteristic size of 25-35 amino acid residues. The closed loops also possess elementary functions, which they bring together in the protein globule forming a functional site. An elementary function is defined by one or few residues involved into function, and it is encoded in the sequence of the loop by the specific signature. Biological function of the globule is built as a combination of few elementary functions which provide necessary sequence of chemical reactions occurring in the functional site. Our model delineates connections between different protein structures based on partitioning them into elementary functional loops (closed loops with a functional signature). The computational procedure for deriving sequence/structure prototypes of elementary functional loop seeks for the primordial prototypes of contemporary elementary functional loops. By considering prototypes of elementary functional loops and their presence in various protein folds, we create a graph of evolutionary connection between different protein functions. We demonstrate, for the first time, that it is possible to reconstruct how biological functions of contemporary proteins emerged as a combination of elementary nes. We explore an evolution protein function and show how current diversity of proteins evolved by utilizing elementary functional loops. We plan to use our model in theoretical predictions of outcomes from the directed evolution experiments and in the de novo design of protein folds with desirable biological function.