Splitting statistical potentials into meaningful scoring functions: Testing the prediction of near-native structures from decoy conformations

Here, we present and demonstrate a theory to split the knowledge-based potentials in scoring terms biologically meaningful and to combine them in new scores to predict near-native structures. Our strategy allows circumventing the problem of defining the reference state. In this approach we give the proof for a simple and linear application that can be further improved by optimizing the combination of Zscores. Using the simplest composite score () we obtained predictions similar to state-of-the-art methods. Besides, our approach has the advantage of identifying the most relevant terms involved in the stability of the protein structure. Finally, we also use the composite Zscores to assess the conformation of models and to detect local errors.We have introduced a method to split knowledge-based potentials and to solve the problem of defining a reference state. The new scores have detected near-native structures as accurately as state-of-art methods and have been successful to identify wrongly modeled regions of many near-native conformations.The study of the conformational space explored by a protein has long been of interest to structural biologists. The small region of this conformational space in which a protein is biologically active is known as its native state. The native state generally has the lowest free energy of all states under the native conditions [1], and the physical mechanism by which a protein finds it is known as the folding pathway. The vastness of the search space for a folding protein was first appreciated by Levinthal [2] who conceived the paradox of a long and non-biological time scale needed for a folding mechanism based on random pathways [3]. The solution of the protein folding problem requires an accurate potential that describes the interactions among different amino acid residues to enable the prediction and assessment of protein structures [4,5]. However, the use of such physical-based potentials [6,7] is computationally prohibitive and o