The Protein Folding Problem (PFP) is a big challenge that has remained unsolved for more than fifty years. This problem consists of obtaining the tertiary structure or Native Structure (NS) of a protein knowing its amino acid sequence. The computational methodologies applied to this problem are classified into two groups, known as Template-Based Modeling (TBM) and ab initio models. In the latter methodology, only information from the primary structure of the target protein is used. In the literature, Hybrid Simulated Annealing (HSA) algorithms are among the best ab initio algorithms for PFP; Golden Ratio Simulated Annealing (GRSA) is a PFP family of these algorithms designed for peptides. Moreover, for the algorithms designed with TBM, they use information from a target protein’s primary structure and information from similar or analog proteins. This paper presents GRSA-SSP methodology that implements a secondary structure prediction to build an initial model and refine it with HSA algorithms. Additionally, we compare the performance of the GRSAX-SSP algorithms versus its corresponding GRSAX. Finally, our best algorithm GRSAX-SSP is compared with PEP-FOLD3, I-TASSER, QUARK, and Rosetta, showing that it competes in small peptides except when predicting the largest peptides.

Protein folding problem (PFP) consists of determining the functional three-dimensional structure of a target protein. PFP is an optimization problem where the objective is to find the structure with the lowest Gibbs free energy. It is significant to solve PFP for use in medical and pharmaceutical applications. Hybrid simulated annealing algorithms (HSA) use a kind of simulated annealing or Monte Carlo method, and they are among the most efficient for PFP. The instances of PFP can be classified as follows: (a) Proteins with a large number of amino acids and (b) peptides with a small number of amino acids. Several HSA have been positively applied for the first case, where I-Tasser has been one of the most successful in the CASP competition. PEP-FOLD3 and golden ratio simulated annealing (GRSA) are also two of these algorithms successfully applied to peptides. This paper presents an enhanced golden simulated annealing (GRSA2) where soft perturbations (collision operators), named “on-wall ineffective collision” and “intermolecular ineffective collision”, are applied to generate new solutions in the metropolis cycle. GRSA2 is tested with a dataset for peptides previously proposed, and a comparison with PEP-FOLD3 and I-Tasser is presented. According to the experimentation, GRSA2 has an equivalent performance to those algorithms.