Enhancing Protein Conformational Space Sampling Using Distance Profile-Guided Differential Evolution.

De novo protein structure prediction aims to search for low-energy conformations as it follows the thermodynamics hypothesis that places native conformations at the global minimum of the protein energy surface. However, the native conformation is not necessarily located in the lowest-energy regions owing to the inaccuracies of the energy model. This study presents a differential evolution algorithm using distance profile-based selection strategy to sample conformations with reasonable structure effectively. In the proposed algorithm, besides energy, the residue-residue distance is considered another measure of the conformation. The average distance errors of decoys between the distance of each residue pair and the corresponding distance in the distance profiles are first calculated when the trial conformation yields a larger energy value than that of the target. Then, the distance acceptance probability of the trial conformation is designed based on distance profiles if the trial conformation obtains a lower average distance error compared with that of the target conformation. The trial conformation is accepted to the next generation in accordance with its distance acceptance probability. By using the dual constraints of energy and distance in guiding sampling, the algorithm can sample conformations with lower energies and more reasonable structures. Experimental results of 28 benchmark proteins show that the proposed algorithm can effectively predict near-native protein structures.

A Novel Method Using Abstract Convex Underestimation in Ab-Initio Protein Structure Prediction for Guiding Search in Conformational Feature Space.

To address the searching problem of protein conformational space in ab-initio protein structure prediction, a novel method using abstract convex underestimation (ACUE) based on the framework of evolutionary algorithm was proposed. Computing such conformations, essential to associate structural and functional information with gene sequences, is challenging due to the high-dimensionality and rugged energy surface of the protein conformational space. As a consequence, the dimension of protein conformational space should be reduced to a proper level. In this paper, the high-dimensionality original conformational space was converted into feature space whose dimension is considerably reduced by feature extraction technique. And, the underestimate space could be constructed according to abstract convex theory. Thus, the entropy effect caused by searching in the high-dimensionality conformational space could be avoided through such conversion. The tight lower bound estimate information was obtained to guide the searching direction, and the invalid searching area in which the global optimal solution is not located could be eliminated in advance. Moreover, instead of expensively calculating the energy of conformations in the original conformational space, the estimate value is employed to judge if the conformation is worth exploring to reduce the evaluation time, thereby making computational cost lower and the searching process more efficient. Additionally, fragment assembly and the Monte Carlo method are combined to generate a series of metastable conformations by sampling in the conformational space. The proposed method provides a novel technique to solve the searching problem of protein conformational space. Twenty small-to-medium structurally diverse proteins were tested, and the proposed ACUE method was compared with It Fix, HEA, Rosetta and the developed method LEDE without underestimate information. Test results show that the ACUE method can more rapidly and more efficiently obtain the near-native protein structure.