Design of novel protein building modules and modular architectures

•Designable non-natural protein folds are estimated to exceed the number of natural folds.•Propagation of protein modules can be harnessed for designing novel protein architectures.•Beta-sheet elements have been successfully implemented in de novo designed protein structures.•α-helical elements are particularly versatile for obtaining protein architectures not present in nature.•Miniproteins represent a valuable contribution to the pool of protein modules available for protein design. Nature uses only a limited number of protein topologies and while several folds have evolved independently over time, there are clearly many possible topologies that have not been explored by evolution. With recent advances of protein design concepts, computational modeling tools, high resolution and high-throughput experimental methods it is now possible to design new protein architectures. The collection of building blocks and design principles widened both in size and complexity, offering an expanded toolset for building new modular folds and functional protein structures. Here we review and discuss recent achievements of protein design, focusing in particular on the use and prospects of modular approaches for assembling new protein folds.