**Abbreviations**

NP-hard problem, as hard to solve as an NP-complete problem; NP-complete problem, no algorithm taking a polynomial-time exists for its solution; Rd, ROSETTA-design; MM, Markov model; HMM, hidden Markov model; CASP, critical assessment of the structure of proteins; PDB, international protein data bank; TIM, triose phosphate isomerase.
