A hybrid genetic algorithm for the 3-D protein structure prediction problem using a path-relinking strategy

Protein structure prediction (PSP) problems are a major biocomputing challenge, owing to its scientific intrinsic that assists researchers to understand the relationship between amino acid sequences and protein structures, and to study the function of proteins. Although computational resources increased substantially over the last decade, a complete solution to PSP problems by computational methods has not yet been obtained. Using only one energy function is insufficient to characterize proteins because of their complexity. Diverse protein energy functions and evolutionary computation algorithms have been extensively studied to assist in the prediction of protein structures in different ways. Such algorithms are able to provide a better protein with less computational resources requirement than deep learning methods. For the first time, this study proposes a many-objective PSP (MaOPSP) problem with four types of objectives to alleviate the impact of imprecise energy functions for predicting protein structures. A many-objective evolutionary algorithm (MaOEA) is utilized to solve MaOPSP. The proposed method is compared with existing methods by examining 34 proteins. An analysis of the objectives demonstrates that our generated conformations are more reasonable than those generated by single/multiobjective optimization methods. Experimental results indicate that solving a PSP problem as an MaOPSP problem with four objectives yields better PSPs, in terms of both accuracy and efficiency. The source code of the proposed method can be found at <uri xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">https://toyamaailab.github.io/sourcedata.html</uri> .

Proteins are essential parts of our life and participate in virtually every process within a cell. The understanding of protein structures is vital to determine the function of a protein. Protein structure prediction (PSP) from amino acid sequence is one of the high focus problems in bioinformatics today. This is due to the fact that the biological function of the protein is determined by its three dimensional structure. Thus, protein structure prediction is a fundamental area of computational biology. Its importance is intensed by large amounts of sequence data coming from PDB (Protein Data Bank) and the fact that experimentally methods such as X-ray crystallography or Nuclear Magnetic Resonance (NMR)which are used to determining protein structures remains very expensive and time consuming. For minimizing the time, computational methods are used for protein folding and structure prediction problem. In this paper results of protein p53 are discussed.

Proteins are cellular macromolecules made up of linear chains of amino acids that adopt a unique three-dimensional structure to carry out specific biological functions. Amongst various computational approaches developed for Protein Structure Prediction (PSP), ab initio methods perform the prediction without prior knowledge of known structures. However, due to huge computational complexity incurred by these methods, simplified hydrophobic-polar (HP) models are often used for the investigations. Despite this simplicity, PSP continues to be a hard combinatorial optimization problem requiring development of efficient heuristic search techniques. Memetic algorithm (MA), with its flexible architecture, encompasses the strength of both local and global search and has shown promise in solving problems with complex search landscape, including PSP. This thesis is focused on developing an effective ab initio technique under a suitable MA framework for solving the PSP problem using low resolution HP models. To enhance the effectiveness of the MA, a mechanism is devised to include knowledge from the problem domain by exploiting the concept of hydrophobic-core (H-core) formation. The size of the maximal possible H-core is estimated and the approximation is validated by our proposed deterministic search technique. Further, a new knowledge-based initial population generation technique ensures generating conformations which are not only valid, but also maintain diversity in the population. This helps to commence the search with good seeds leading towards faster convergence. While solving the PSP problem using MA, the greatest intricacy arises from the complex nature of its multi-modal landscape. Like all the evolutionary algorithms (EAs), MAs have the tendency to get trapped into local minima due to selection pressure and genetic drift induced by the genetic operators, and techniques are necessary to surmount this difficulty. A novel parental selection technique called “Adaptive Strategy for Assortative Mating” is developed that dynamically distributes the re production opportunity among the individuals of the population to boost the effectiveness of cross-over. Further, a new survival selection strategy, namely “Sib-based Survival Selection”, prevents the rapid spread of genetic material from a particular individual to other members in the population, ensuring the concurrent preservation of several potential solutions, and restricting premature convergence. A new diversification mechanism, namely “Memory-based Diversification”, systematically diversifies the population by introducing new genetic material whenever it gets stuck at local peaks and allows it to proceed for further progress. An extensive experimental analysis is also reported on the influence of all three techniques proposed to maintain the diversity of population. Furthermore, in order to carry out the conformational search efficiently, especially with the increase in sequence length, the optimization technique is designed such that it provides an effective balance between exploration and exploitation. A robust Multimodal Memetic Framework has been developed where optimization is accomplished in hierarchical stages. The population of each stage is partitioned into three different states: an Exploratory state to locate promising peaks, an Exploitative state to fine-tune the solutions found in the Exploratory state of the previous stage, and finally, a Central state to carry out the formation of potential solutions to explore the undiscovered regions. Non-identical genetic operators have been implemented in each state to balance the exploration and exploitation by employing necessary selection pressure and diversity. A non-isomorphic encoding based technique has been developed to capture the sub-structures that are representing a particular region. Furthermore, a novel local search technique exploits already explored fit individuals by employing the knowledge of sub-structures. The efficacy of the proposed framework is demonstrated with an adequate number of distinctive data sets and comparison with state-of-the-art methods.

Adoption of an improved PSO to explore a compound multi-objective energy function in protein structure prediction

One of the most challenging problems in Bioinformatics is the finding of a protein conformation and it is known as the Protein Structure Prediction (PSP) problem. The main feature present in the AB off‐lattice model is the use of polarity as the main driving force to guide the optimization process. The present work proposes an adaptive evolutionary algorithm based on GPU that is applied to the 3D‐AB off‐lattice PSP problem. The proposed approach is named cuDSMjDE, and is composed of a Dynamic Speciation‐based Mutation Strategies Differential Evolution that employs the jDE mechanism to control F and CR parameters. A crowding strategy is also adopted, increasing competition between individuals and maintaining the diversity of solutions. All routines of the proposed algorithm are developed to run in GPU. During the experiments, eight Protein Data Bank sequences are employed. Results obtained concerning potential energy are competitive when compared with state‐of‐the‐art algorithms. The use of a massively parallel architecture promoted the necessary scalability with speedups up to 708.78.

The Protein Structure Prediction (PSP) problem is concerned about the prediction of the native tertiary structure of a protein in respect to its amino acids sequence. PSP is a challenging and computationally open problem. Therefore, several researches and methodologies have been developed for it. In this way, developers are working to integrate frameworks in order to improve their capabilities and make their use more straightforward. This paper presents the application of NSGA-II algorithm using structural and energetic properties of protein. The implementation of this algorithm is based on ProtPred-GROMACS (2PG), an evolutionary framework for PSP. This framework is the integration between ProtPred and GROMACS. Six proteins were used to measure the capacity of ab initio predictions. The results were interesting since in all cases the native-like topology was obtained.

To solve protein structure prediction (PSP) problems computationally, a plethora of template-based methods exist. However, there are very few ab initio models for PSP. Template-based modeling relies on the existing structures and therefore is not effective for non-homologous sequence-based structure prediction. Thus, ab initio modeling is indispensable in such cases, even though it is a challenging optimization problem. To cope, we utilize an effective energy function (called 3DIGARS) and an advanced search algorithm (called KGA) based ab initio PSP, called 3DIGARS-PSP. To address critical search, the proposed genetic algorithm deploys two effective operators: angle rotation and segment translation. Further, propensities of torsion angle and secondary structure distribution have been utilized to guide the conformation search. Crucial features, such as sequence-specific accessibility, hydrophobic-hydrophilic properties and torsion angles of protein residues are mined to formulate an optimized energy function, which is then combined with the advanced sampling algorithm to explore critical conformational space. Consequently, 3DIGARS-PSP performed well compared to the state-of-the-art method for a set of low TMscore models from CASP data.

Most computational protein structure prediction methods are designed for either template based or template-free (ab initio) structure prediction. The approaches that integrate the prediction capabilities of both template-based modeling and template-free modeling are needed to synergistically combine the two kinds of methods to improve protein structure prediction. In this work, we develop a new method to integrate several protein structure prediction methods including our template-based MULTICOM server, our ab initio contact-based protein structure prediction method CONFOLD, our multi-template-based model generation tool MTMG, and locally installed external Rosetta, I-TASSER and RaptorX protein structure prediction tools to improve protein structure prediction of a fullspectrum difficulty ranging from easy, to medium and to hard. Our method participated in the 11(th) community-wide Critical Assessment of Techniques for Protein Structure Prediction (CASP11) in 2014 as MULTICOM-NOVEL server. It was ranked among top 10 methods for protein tertiary structure prediction according to the official CASP11 assessment, which demonstrates that integrating complementary modeling methods is useful for advancing protein structure prediction.

MODCSA-CA: A multi objective diversity controlled self adaptive cuckoo algorithm for protein structure prediction

Predicting the 3D native conformation of a protein given the amino acid sequence is known as protein structure prediction (PSP) problem and is one of the greatest challenges of computational biology. The current work uses a real valued Genetic Algorithm (GA), a powerful variate of GA to simulate the PSP problem. This algorithm consists of basic evolutionary operators and a fitness vector. The fitness vector is designed by combining a set of knowledge based biophysical filters viz. persistence length, radius of gyration, packing fraction, hydrophobicity ratio and irregularity index of phi and psi. This vector converts all these biophysical measures into a real value by using specific weights or factors. The algorithm has been validated on six known globular proteins, with their length varying from 17-61 residues and total number of helices and strands in the range of 2-4. For all the test protein the algorithm converges rapidly and the converged structure shows a backbone RMSD (root mean square deviation) of 3-6A as compared to the native structure.

The p7-transactivated protein1 of Hepatitis C virus is a small integral membrane protein of 127 amino acids, which is crucial for assembly and release of infectious virions. Ab initio or comparative modelling, is an essential tool to solve the problem of protein structure prediction and to comprehend the physicochemical fundamental of how proteins fold in nature. Only one domain (1-127) of p7-transactivated protein1 has been predicted using the systematic in silico approach, ThreaDom. I-TASSER was ranked as the best server for full-length 3-D protein structural predictions of p7-transactivated protein1 where the benchmarked scoring system such as C-score, TM-score, RMSD and Z-score are used to obtain quantitative assessments of the I-TASSER models. Scanning protein motif databases, along with secondary and surface accessibility predictions integrated with post translational modification sites (PTMs) prediction revealed functional and protein binding motifs. Three protein binding motifs (two Asp/Glutamnse, CTNNB1- bd_N) with high sequence conservation and two PTMs prediction: Camp_phospho_site and Myristyl site were predicted using BLOCKS and PROSITE scan. These motifs and PTMs were related to the function of p7-transactivated protein1 protein in inducing ion channel/pore and release of infectious virions. Using SCOP, only one hit matched protein sequence at 71-120 was classified as small proteins and FYVE/PHD zinc finger superfamily. Integrating this information about the p7-transactivated protein1 with SCOP and CATH annotations of the templates facilitates the assignment of structure-function/ evolution relationships to the known and the newly determined protein structures.

AIMOES: Archive information assisted multi-objective evolutionary strategy for ab initio protein structure prediction

This paper provides a novel perspective in the Protein Structure Prediction (PSP) problem. The PSP problem focuses on determining putative 3D structures of a protein starting from its primary sequence. The proposed approach relies on a multi-agents approach, where concurrent agents explore the folding of different parts of a protein. The strength of the approach lies in the agents' ability to apply different types of knowledge (expressed in the form of declarative constraints) to prune the local space of folding alternatives. The paper demonstrates the suitability of a GPU approach to implement such multi-agent infrastructure, with significant improvements in speed and quality of solutions w.r.t. other methods (e.g., based on fragments assembly approaches).

Evolutionarily conserved hydrophobic residues at the core of protein structures are generally assumed to play a structural role in protein folding and stability. Recent studies have implicated that their importance to protein structures is uneven, with a few of them being crucial and the rest of them being secondary. In this work, we explored the possibility of employing this feature of native structures for discriminating non-native structures from native ones. First, we developed a network tool to quantitatively measure the structural contributions of individual amino acid residues. We systematically applied this method to diverse fold-type sets of native proteins. It was confirmed that this method could grasp the essential structural features of native proteins. Next, we applied it to a number of decoy sets of proteins. The results indicate that such an approach indeed identified non-native structures in most test cases. This finding should be of help for the investigation of the fundamental problem of protein structure prediction.

In this study, we used the Hydrophobic-Polar (HP) two-dimensional square and three-dimensional cubic lattice models for the problem of Protein structure prediction (PSP). This kind of lattice reduces computational time and calculations, and the conformational space from 9n to 4n−2, even in this context, it is an appropriate benchmark problem for genetic algorithms. The contributions of the paper consist in: (1) implementation of a high-performing novel Genetic algorithm (GA); instead of considering only the self- avoiding walk (SAW) conformations approached in other work, we decided to allow any conformation to appear in the population at all stages of the proposed all conformations biomimetic Genetic Algorithm (ACGA). This increases the probability of achieving good native conformations (SAW ones), with the lowest energy that has the minimum number of contacts in the lattice, the one with the maximum topological neighbors. In addition to classical crossover and mutation operators, (2) we introduced specific translation operators for these two operations. We have proposed and implemented an HP Protein Visualizer tool which offers interpretability, a hybrid approach in that the visualizer give some insight to the algorithm, that analyse and optimise protein structures HP model. The program resulted based on performed research, provides a molecular modeling tool for studying protein folding using technologies such as React, Next.js, and Three.js for 3D rendering, and includes optimization algorithms to simulate protein folding.