The ability to engineer the precise geometries, fine-tuned energetics and subtle dynamics that are characteristic of functional proteins is a major unsolved challenge in the field of computational protein design. In natural proteins, functional sites exhibiting these properties often feature structured loops. However, unlike the elements of secondary structures that comprise idealized protein folds, structured loops have been difficult to design computationally. Addressing this shortcoming in a general way is a necessary first step towards the routine design of protein function. In this perspective, we will describe the progress that has been made on this problem and discuss how recent advances in the field of loop structure prediction can be harnessed and applied to the inverse problem of computational loop design.
Keywords: Rosetta software; binding site design; loop modeling; positioning functional residues; protein design.