Supplementary data are available at Bioinformatics online.

Predicting 3D structure of protein from its amino acid sequence is one of the most important unsolved problems in biophysics and computational biology. This paper attempts to give a comprehensive introduction of the most recent effort and progress on protein structure prediction. Following the general flowchart of structure prediction, related concepts and methods are presented and discussed. Moreover, brief introductions are made to several widely-used prediction methods and the community-wide critical assessment of protein structure prediction (CASP) experiments.

Many statistical potentials were developed in last two decades for protein folding and protein structure recognition. The major difference of these potentials is on the selection of reference states to offset sampling bias. However, since these potentials used different databases and parameter cutoffs, it is difficult to judge what the best reference states are by examining the original programs. In this work, we aim to address this issue and evaluate the reference states by a unified database and programming environment. We constructed distance-specific atomic potentials using six widely-used reference states based on 1,022 high-resolution protein structures, which are applied to rank modeling in six sets of structure decoys. The reference state on random-walk chain outperforms others in three decoy sets while those using ideal-gas, quasi-chemical approximation and averaging sample stand out in one set separately. Nevertheless, the performance of the potentials relies on the origin of decoy generations and no reference state can clearly outperform others in all decoy sets. Further analysis reveals that the statistical potentials have a contradiction between the universality and pertinence, and optimal reference states should be extracted based on specific application environments and decoy spaces.