Liang-Tsung Huang

iPTREE-STAB

UNLABELLEDnWe have developed a web server, iPTREE-STAB for discriminating the stability of proteins (stabilizing or destabilizing) and predicting their stability changes (delta deltaG) upon single amino acid substitutions from amino acid sequence. The discrimination and prediction are mainly based on decision tree coupled with adaptive boosting algorithm, and classification and regression tree, respectively, using three neighboring residues of the mutant site along N- and C-terminals. Our method showed an accuracy of 82% for discriminating the stabilizing and destabilizing mutants, and a correlation of 0.70 for predicting protein stability changes upon mutations.nnnAVAILABILITYnhttp://bioinformatics.myweb.hinet.net/iptree.htm.nnnSUPPLEMENTARY INFORMATIONnDataset and other details are given.

Analysis and prediction of protein folding rates using quadratic response surface models

Understanding the relationship between amino acid sequences and folding rates of proteins is an important task in computational and molecular biology. In this work, we have systematically analyzed the composition of amino acid residues for proteins with different ranges of folding rates. We observed that the polar residues, Asn, Gln, Ser, and Lys, are dominant in fast folding proteins whereas the hydrophobic residues, Ala, Cys, Gly, and Leu, prefer to be in slow folding proteins. Further, we have developed a method based on quadratic response surface models for predicting the folding rates of 77 two‐ and three‐state proteins. Our method showed a correlation of 0.90 between experimental and predicted protein folding rates using leave‐one‐out cross‐validation method. The classification of proteins based on structural class improved the correlation to 0.98 and it is 0.99, 0.98, and 0.96, respectively, for all‐α, all‐β, and mixed class proteins. In addition, we have utilized Baysean classification theory for discriminating two‐ and three‐state proteins, which showed an accuracy of 90%. We have developed a web server for predicting protein folding rates and it is available at http://bioinformatics.myweb.hinet.net/foldrate.htm.

Reliable prediction of protein thermostability change upon double mutation from amino acid sequence

SUMMARYnThe accurate prediction of protein stability change upon mutation is one of the important issues for protein design. In this work, we have focused on the stability change of double mutations and systematically analyzed the wild-type and mutant residues, patterns in amino acid sequence and locations of mutants. Based on the sequence information of wild-type, mutant and three neighboring residues, we have presented a weighted decision table method (WET) for predicting the stability changes of 180 double mutants obtained from thermal (DeltaDeltaG) denaturation. Using 10-fold cross-validation test, our method showed a correlation of 0.75 between experimental and predicted values of stability changes, and an accuracy of 82.2% for discriminating the stabilizing and destabilizing mutants.

Developing a fuzzy search engine based on fuzzy ontology and semantic search

Most of existing search engines retrieve web pages by means of finding exact keywords. Traditional keyword-based search engines suffer several problems. First, synonyms and terms similar to keywords are not taken into consideration to search web pages. Users may need to input several similar keywords individually to complete a search. Second, traditional search engines treat all keywords as the same importance and cannot differentiate the importance of one keyword from that of another. Third, traditional search engines lack an applicable classification mechanism to reduce the search space and improve the search results. In this paper, we develop a fuzzy search engine, called Fuzzy-Go. First, a fuzzy ontology is constructed by using fuzzy logic to capture the similarities of terms in the ontology, which offering appropriate semantic distances between terms to accomplish the semantic search of keywords. The Fuzzy-Go search engine can thus automatically retrieve web pages that contain synonyms or terms similar to keywords. Second, users can input multiple keywords with different degrees of importance based on their needs. The totally satisfactory degree of keywords can be aggregated based on their degrees of importance and degrees of satisfaction. Third, the domain classification of web pages offers users to select the appropriate domain for searching web pages, which excludes web pages in the inappropriate domains to reduce the search space and to improve the search results.

First insight into the prediction of protein folding rate change upon point mutation

SUMMARYnThe accurate prediction of protein folding rate change upon mutation is an important and challenging problem in protein folding kinetics and design. In this work, we have collected experimental data on protein folding rate change upon mutation from various sources and constructed a reliable and non-redundant dataset with 467 mutants. These mutants are widely distributed based on secondary structure, solvent accessibility, conservation score and long-range contacts. From systematic analysis of these parameters along with a set of 49 amino acid properties, we have selected a set of 12 features for discriminating the mutants that speed up or slow down the folding process. We have developed a method based on quadratic regression models for discriminating the accelerating and decelerating mutants, which showed an accuracy of 74% using the 10-fold cross-validation test. The sensitivity and specificity are 63% and 76%, respectively. The method can be improved with the inclusion of physical interactions and structure-based parameters.nnnAVAILABILITYnhttp://bioinformatics.myweb.hinet.net/freedom.htm.

Knowledge acquisition and development of accurate rules for predicting protein stability changes

Knowing the mechanisms by which protein stability change is one of the most important and valuable tasks in molecular biology. The conventional methods of predicting protein stability changes mainly focus on improving prediction accuracy. However, it is desirable to extract domain knowledge from large databases that is beneficial to accurate prediction of the protein stability change. This paper presents an interpretable prediction tree method (named iPTREE) that produces explanatory rules to explore hidden knowledge accompanied with high prediction accuracy and consequently analyzes the factors influencing the protein stability changes. To evaluate iPTREE and the knowledge upon protein stability changes, a thermodynamic dataset consisting of 1615 mutants led by single point mutation from ProTherm is adopted. Being as a predictor for protein stability changes, the rule-based approach can achieve a prediction accuracy of 87%, which is better than other methods based on artificial neural networks (ANN) and support vector machines (SVM). Besides, these methods lack the ability in biological knowledge discovery. The human-interpretable rules produced by iPTREE reveal that temperature is a factor of concern in predicting protein stability changes. For example, one of interpretable rules with high support is as follows: if the introduced residue type is Alanine and temperature is between 4 degrees C and 40 degrees C, then the stability change will be negative (destabilizing). The present study demonstrates that iPTREE can easily be used in the application of protein stability changes where one requires more understandable knowledge.

Machine Learning Algorithms for Predicting Protein Folding Rates and Stability of Mutant Proteins: Comparison with Statistical Methods

Machine learning algorithms have wide range of applications in bioinformatics and computational biology such as prediction of protein secondary structures, solvent accessibility, binding site residues in protein complexes, protein folding rates, stability of mutant proteins, and discrimination of proteins based on their structure and function. In this work, we focus on two aspects of predictions: (i) protein folding rates and (ii) stability of proteins upon mutations. We briefly introduce the concepts of protein folding rates and stability along with available databases, features for prediction methods and measures for prediction performance. Subsequently, the development of structure based parameters and their relationship with protein folding rates will be outlined. The structure based parameters are helpful to understand the physical basis for protein folding and stability. Further, basic principles of major machine learning techniques will be mentioned and their applications for predicting protein folding rates and stability of mutant proteins will be illustrated. The machine learning techniques could achieve the highest accuracy of predicting protein folding rates and stability. In essence, statistical methods and machine learning algorithms are complimenting each other for understanding and predicting protein folding rates and the stability of protein mutants. The available online resources on protein folding rates and stability will be listed.

A self-adaptation approach to Fuzzy-Go search engine

The Fuzzy-Go search engine develops a fuzzy ontology to capture the similarities of terms in the ontology for accomplishing the semantic search of keywords, a web crawler to gather and classify web pages, and a fuzzy search mechanism to aggregate all fuzzy factors based on their degrees of importance and degrees of satisfaction. In this paper, we apply the genetic algorithm to propose a self-adaptation approach to Fuzzy-Go search engine. For each search, the fuzzy search engine records the difference between the ordering of search results and users real behavior on clicking web pages. The feedbacks are gathered and analyzed to adjust the fuzzy similarities between terms in the fuzzy ontology, the domain classification of web pages, and the importance degrees of fuzzy factors. The ordering of search results can thus be improved gradually by continuous learning and adaptation.

Discrimination of driver and passenger mutations in epidermal growth factor receptor in cancer

Cancer is one of the most life-threatening diseases and mutations in several genes are the vital cause in tumorigenesis. Protein kinases play essential roles in cancer progression and specifically, epidermal growth factor receptor (EGFR) is an important target for cancer therapy. In this work, we have developed a method to classify single amino acid polymorphisms (SAPs) in EGFR into disease-causing (driver) and neutral (passenger) mutations using both sequence and structure based features of the mutation site by machine learning approaches. We compiled a set of 222 features and selected a set of 21 properties utilizing feature selection methods, for maximizing the prediction performance. In a set of 540 mutants, we obtained an overall classification accuracy of 67.8% with 10 fold cross validation using support vector machines. Further, the mutations have been grouped into four sets based on secondary structure and accessible surface area, which enhanced the overall classification accuracy to 80.2%, 81.9%, 77.9% and 75.1% for helix, strand, coil-buried and coil-exposed mutants, respectively. The method was tested with a blind dataset of 60 mutations, which showed an average accuracy of 85.4%. These accuracy levels are superior to other methods available in the literature for EGFR mutants, with an increase of more than 30%. Moreover, we have screened all possible single amino acid polymorphisms (SAPs) in EGFR and suggested the probable driver and passenger mutations, which would help in the development of mutation specific drugs for cancer treatment.

Real value prediction of protein folding rate change upon point mutation.

Prediction of protein folding rate change upon amino acid substitution is an important and challenging problem in protein folding kinetics and design. In this work, we have analyzed the relationship between amino acid properties and folding rate change upon mutation. Our analysis showed that the correlation is not significant with any of the studied properties in a dataset of 476 mutants. Further, we have classified the mutants based on their locations in different secondary structures and solvent accessibility. For each category, we have selected a specific combination of amino acid properties using genetic algorithm and developed a prediction scheme based on quadratic regression models for predicting the folding rate change upon mutation. Our results showed a 10-fold cross validation correlation of 0.72 between experimental and predicted change in protein folding rates. The correlation is 0.73, 0.65 and 0.79, respectively in strand, helix and coil segments. The method has been further tested with an extended dataset of 621 mutants and a blind dataset of 62 mutants, and we observed a good agreement with experiments. We have developed a web server for predicting the folding rate change upon mutation and it is available at http://bioinformatics.myweb.hinet.net/fora.htm.