Computational protein design for given backbone: recent progresses in general method-related aspects

To achieve high success rate in protein design requires a reliable sequence design method to find amino acid sequences that stably fold into a desired backbone structure. This problem is addressed by computational protein design through the approach of energy minimization. Here we review recent method progresses related to improving the accuracy of this approach. First, the quality of the energy model is a key factor. Second, with structure sensitive energy functions, whether and how backbone flexibility is considered can have large effects on design accuracy, although usually only small adjustments of the backbone structure itself are involved. Third, the effective accuracy of design results can be boosted by post-processing a small number of designed sequences with complementary models that may not be efficient enough for full sequence optimization. Finally, computational method development will benefit greatly from increasingly efficient experimental approaches that can be applied to obtain extensive feedbacks.