Browsing by Author "Lo, Wei-Cheng"

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A simple strategy to enhance the speed of protein secondary structure prediction without sacrificing accuracy
(2020-06-30)
Juan, Sheng-Hung
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Chen, Teng-Ruei
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Lo, Wei-Cheng
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生物科技學系
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生物資訊及系統生物研究所
The secondary structure prediction of proteins is a classic topic of computational structural biology with a variety of applications. During the past decade, the accuracy of prediction achieved by state-of-the-art algorithms has been >80%; meanwhile, the time cost of prediction increased rapidly because of the exponential growth of fundamental protein sequence data. Based on literature studies and preliminary observations on the relationships between the size/homology of the fundamental protein dataset and the speed/accuracy of predictions, we raised two hypotheses that might be helpful to determine the main influence factors of the efficiency of secondary structure prediction. Experimental results of size and homology reductions of the fundamental protein dataset supported those hypotheses. They revealed that shrinking the size of the dataset could substantially cut down the time cost of prediction with a slight decrease of accuracy, which could be increased on the contrary by homology reduction of the dataset. Moreover, the Shannon information entropy could be applied to explain how accuracy was influenced by the size and homology of the dataset. Based on these findings, we proposed that a proper combination of size and homology reductions of the protein dataset could speed up the secondary structure prediction while preserving the high accuracy of state-of-the-art algorithms. Testing the proposed strategy with the fundamental protein dataset of the year 2018 provided by the Universal Protein Resource, the speed of prediction was enhanced over 20 folds while all accuracy measures remained equivalently high. These findings are supposed helpful for improving the efficiency of researches and applications depending on the secondary structure prediction of proteins. To make future implementations of the proposed strategy easy, we have established a database of size and homology reduced protein datasets at http://10.life.nctu.etu.tw/UniRefNR.
Circular Permutation Prediction Reveals a Viable Backbone Disconnection for Split Proteins: An Approach in Identifying a New Functional Split Intein
(2012-08-24)
Lee, Yun-Tzai
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Su, Tz-Hsiang
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Lo, Wei-Cheng
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Lyu, Ping-Chiang
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Sue, Shih-Che
Split-protein systems have emerged as a powerful tool for detecting biomolecular interactions and reporting biological reactions. However, reliable methods for identifying viable split sites are still unavailable. In this study, we demonstrated the feasibility that valid circular permutation (CP) sites in proteins have the potential to act as split sites and that CP prediction can be used to search for internal permissive sites for creating new split proteins. Using a protein ligase, intein, as a model, CP predictor facilitated the creation of circular permutants in which backbone opening imposes the least detrimental effects on intein folding. We screened a series of predicted intein CPs and identified stable and native-fold CPs. When the valid CP sites were introduced as split sites, there was a reduction in folding enthalpy caused by the new backbone opening; however, the coincident loss in entropy was sufficient to be compensated, yielding a favorable free energy for self-association. Since split intein is exploited in protein semi-synthesis, we tested the related protein trans-splicing (PTS) activities of the corresponding split inteins. Notably, a novel functional split intein composed of the N-terminal 36 residues combined with the remaining C-terminal fragment was identified. Its PTS activity was shown to be better than current reported two-piece intein with a short N-terminal segment. Thus, the incorporation of in silico CP prediction facilitated the design of split intein as well as circular permutants.
Construction and analysis of a plant non-specific lipid transfer protein database (nsLTPDB)
(2012-01-17)
Wang, Nai-Jyuan
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Lee, Chi-Ching
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Cheng, Chao-Sheng
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Lo, Wei-Cheng
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Yang, Ya-Fen
Background: Plant non-specific lipid transfer proteins (nsLTPs) are small and basic proteins. Recently, nsLTPs have been reported involved in many physiological functions such as mediating phospholipid transfer, participating in plant defence activity against bacterial and fungal pathogens, and enhancing cell wall extension in tobacco. However, the lipid transfer mechanism of nsLTPs is still unclear, and comprehensive information of nsLTPs is difficult to obtain. Methods: In this study, we identified 595 nsLTPs from 121 different species and constructed an nsLTPs database - nsLTPDB - which comprises the sequence information, structures, relevant literatures, and biological data of all plant nsLTPs http://nsltpdb.life.nthu.edu.tw/. Results: Meanwhile, bioinformatics and statistics methods were implemented to develop a classification method for nsLTPs based on the patterns of the eight highly-conserved cysteine residues, and to suggest strict Prosite-styled patterns for Type I and Type II nsLTPs. The pattern of Type I is C X-2 V X5-7 C [V, L, I] x Y [L, A, V] X8-13 CC x G X-12 D x [Q, K, R] X-2 CXC X16-21 P X-2 C X13-15C, and that of Type II is C X-4 L X-2 C X9-11 P [S, T] X-2 CC X-5 Q X2-4 C[L, F] C X-2 [A, L, I] x [D, N] P X10-12 [K, R] X4-5 C X3-4 P X0-2 C. Moreover, we referred the Prosite-styled patterns to the experimental mutagenesis data that previously established by our group, and found that the residues with higher conservation played an important role in the structural stability or lipid binding ability of nsLTPs. Conclusions: Taken together, this research has suggested potential residues that might be essential to modulate the structural and functional properties of plant nsLTPs. Finally, we proposed some biologically important sites of the nsLTPs, which are described by using a new Prosite-styled pattern that we defined.
CPred: a web server for predicting viable circular permutations in proteins
(2012-07-01)
Lo, Wei-Cheng
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Wang, Li-Fen
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Liu, Yen-Yi
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Dai, Tian
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Hwang, Jenn-Kang
"Circular permutation (CP) is a protein structural rearrangement phenomenon, through which nature allows structural homologs to have different locations of termini and thus varied activities, stabilities and functional properties. It can be applied in many fields of protein research and bioengineering. The limitation of applying CP lies in its technical complexity, high cost and uncertainty of the viability of the resulting protein variants. Not every position in a protein can be used to create a viable circular permutant, but there is still a lack of practical computational tools for evaluating the positional feasibility of CP before costly experiments are carried out. We have previously designed a comprehensive method for predicting viable CP cleavage sites in proteins. In this work, we implement that method into an efficient and user-friendly web server named CPred (CP site predictor), which is supposed to be helpful to promote fundamental researches and biotechnological applications of CP. The CPred is accessible at http://sarst.life.nthu.edu.tw/CPred."
Deciphering the Preference and Predicting the Viability of Circular Permutations in Proteins
(2012-02-16)
Lo, Wei-Cheng
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Dai, Tian
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Liu, Yen-Yi
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Wang, Li-Fen
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Hwang, Jenn-Kang
Circular permutation (CP) refers to situations in which the termini of a protein are relocated to other positions in the structure. CP occurs naturally and has been artificially created to study protein function, stability and folding. Recently CP is increasingly applied to engineer enzyme structure and function, and to create bifunctional fusion proteins unachievable by tandem fusion. CP is a complicated and expensive technique. An intrinsic difficulty in its application lies in the fact that not every position in a protein is amenable for creating a viable permutant. To examine the preferences of CP and develop CP viability prediction methods, we carried out comprehensive analyses of the sequence, structural, and dynamical properties of known CP sites using a variety of statistics and simulation methods, such as the bootstrap aggregating, permutation test and molecular dynamics simulations. CP particularly favors Gly, Pro, Asp and Asn. Positions preferred by CP lie within coils, loops, turns, and at residues that are exposed to solvent, weakly hydrogen-bonded, environmentally unpacked, or flexible. Disfavored positions include Cys, bulky hydrophobic residues, and residues located within helices or near the protein's core. These results fostered the development of an effective viable CP site prediction system, which combined four machine learning methods, e. g., artificial neural networks, the support vector machine, a random forest, and a hierarchical feature integration procedure developed in this work. As assessed by using the hydrofolate reductase dataset as the independent evaluation dataset, this prediction system achieved an AUC of 0.9. Large-scale predictions have been performed for nine thousand representative protein structures; several new potential applications of CP were thus identified. Many unreported preferences of CP are revealed in this study. The developed system is the best CP viability prediction method currently available. This work will facilitate the application of CP in research and biotechnology.
Detection and Alignment of 3D Domain Swapping Proteins Using Angle-Distance Image-Based Secondary Structural Matching Techniques
(2010-10-14)
Chu, Chia-Han
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Lo, Wei-Cheng
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Wang, Hsin-Wei
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Hsu, Yen-Chu
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Hwang, Jenn-Kang
This work presents a novel detection method for three-dimensional domain swapping (DS), a mechanism for forming protein quaternary structures that can be visualized as if monomers had "opened'' their "closed'' structures and exchanged the opened portion to form intertwined oligomers. Since the first report of DS in the mid 1990s, an increasing number of identified cases has led to the postulation that DS might occur in a protein with an unconstrained terminus under appropriate conditions. DS may play important roles in the molecular evolution and functional regulation of proteins and the formation of depositions in Alzheimer's and prion diseases. Moreover, it is promising for designing auto-assembling biomaterials. Despite the increasing interest in DS, related bioinformatics methods are rarely available. Owing to a dramatic conformational difference between the monomeric/closed and oligomeric/open forms, conventional structural comparison methods are inadequate for detecting DS. Hence, there is also a lack of comprehensive datasets for studying DS. Based on angle-distance (A-D) image transformations of secondary structural elements (SSEs), specific patterns within A-D images can be recognized and classified for structural similarities. In this work, a matching algorithm to extract corresponding SSE pairs from A-D images and a novel DS score have been designed and demonstrated to be applicable to the detection of DS relationships. The Matthews correlation coefficient (MCC) and sensitivity of the proposed DS-detecting method were higher than 0.81 even when the sequence identities of the proteins examined were lower than 10%. On average, the alignment percentage and root-mean-square distance (RMSD) computed by the proposed method were 90% and 1.8 angstrom for a set of 1,211 DS-related pairs of proteins. The performances of structural alignments remain high and stable for DS-related homologs with less than 10% sequence identities. In addition, the quality of its hinge loop determination is comparable to that of manual inspection. This method has been implemented as a web-based tool, which requires two protein structures as the input and then the type and/or existence of DS relationships between the input structures are determined according to the A-D image-based structural alignments and the DS score. The proposed method is expected to trigger large-scale studies of this interesting structural phenomenon and facilitate related applications.
Evolutionary information hidden in a single protein structure
(2012-06-01)
Shih, Chien-Hua
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Chang, Chih-Min
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Lin, Yeong-Shin
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Lo, Wei-Cheng
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Hwang, Jenn-Kang
The knowledge of conserved sequences in proteins is valuable in identifying functionally or structurally important residues. Generating the conservation profile of a sequence requires aligning families of homologous sequences and having knowledge of their evolutionary relationships. Here, we report that the conservation profile at the residue level can be quantitatively derived from a single protein structure with only backbone information. We found that the reciprocal packing density profiles of protein structures closely resemble their sequence conservation profiles. For a set of 554 nonhomologous enzymes, 74% (408/554) of the proteins have a correlation coefficient > 0.5 between these two profiles. Our results indicate that the three-dimensional structure, instead of being a mere scaffold for positioning amino acid residues, exerts such strong evolutionary constraints on the residues of the protein that its profile of sequence conservation essentially reflects that of its structural characteristics. Proteins 2012;. (c) 2012 Wiley Periodicals, Inc.
Exploration of Brain Connectivity during Human Inhibitory Control Using Inter-Trial Coherence
(2020-03-01)
Chikara, Rupesh Kumar
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Lo, Wei-Cheng
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Ko, Li-Wei
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交大名義發表
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生物科技學系
Inhibitory control is a cognitive process that inhibits a response. It is used in everyday activities, such as driving a motorcycle, driving a car and playing a game. The effect of this process can be compared to the red traffic light in the real world. In this study, we investigated brain connectivity under human inhibitory control using the phase lag index and inter-trial coherence (ITC). The human brain connectivity gives a more accurate representation of the functional neural network. Results of electroencephalography (EEG), the data sets were generated from twelve healthy subjects during left and right hand inhibitions using the auditory stop-signal task, showed that the inter-trial coherence in delta (1-4 Hz) and theta (4-7 Hz) band powers increased over the frontal and temporal lobe of the brain. These EEG delta and theta band activities neural markers have been related to human inhibition in the frontal lobe. In addition, inter-trial coherence in the delta-theta and alpha (8-12 Hz) band powers increased at the occipital lobe through visual stimulation. Moreover, the highest brain connectivity was observed under inhibitory control in the frontal lobe between F3-F4 channels compared to temporal and occipital lobes. The greater EEG coherence and phase lag index in the frontal lobe is associated with the human response inhibition. These findings revealed new insights to understand the neural network of brain connectivity and underlying mechanisms during human response inhibition.
GI-POP: A combinational annotation and genomic island prediction pipeline for ongoing microbial genome projects
(2013-04-10)
Lee, Chi-Ching
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Chen, Yi-Ping Phoebe
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Yao, Tzu-Jung
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Ma, Cheng-Yu
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Lo, Wei-Cheng
Sequencing of microbial genomes is important because of microbial-carrying antibiotic and pathogenetic activities. However, even with the help of new assembling software, finishing a whole genome is a time-consuming task. In most bacteria, pathogenetic or antibiotic genes are carried in genomic islands. Therefore, a quick genomic island (GI) prediction method is useful for ongoing sequencing genomes. In this work, we built a Web server called GI-POP (http://gipop.life.nthu.edu.tw) which integrates a sequence assembling tool, a functional annotation pipeline, and a high-performance GI predicting module, in a support vector machine (SVM)-based method called genomic island genomic profile scanning (GI-GPS). The draft genomes of the ongoing genome projects in contigs or scaffolds can be submitted to our Web server, and it provides the functional annotation and highly probable GI-predicting results. GI-POP is a comprehensive annotation Web server designed for ongoing genome project analysis. Researchers can perform annotation and obtain pre-analytic information include possible GIs, coding/non-coding sequences and functional analysis from their draft genomes. This pre-analytic system can provide useful information for finishing a genome sequencing project. (c) 2012 Elsevier B.V. All rights reserved.
High-Performance Plasmonic Nanolasers with a Nanotrench Defect Cavity for Sensing Applications
(2018-07-01)
Cheng, Pi-Ju
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Huang, Zhen-Ting
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Li, Jhu-Hong
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Chou, Bo-Tsun
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Chou, Yu-Hsun
Recent developments in small footprint plasmonic nanolasers show promise for active optical sensing with potential applications in various fields, including real-time and label-free biochemical sensing, and gas detection. In this study, we demonstrate a novel hybrid plasmonic crystal nanolaser that features a ZnO nanowire placed on Al grating surfaces with a nanotrench defect nanocavity. The lasing action of gain-assisted defect nanocavity overcomes the ohmic loss parasitically in the plasmonic nanostructures. Therefore, the plasmonic nanolaser exhibits an extremely small mode volume, a narrow linewidth Delta lambda, and a high Purcell factor that can facilitate the strong interaction between light and matter. This can be used as a refractive index sensor and is highly sensitive to local changes in the refractive indices of ambient materials. By careful design, the near-ultraviolet nanolaser sensors have significant sensing performances of glucose solutions, revealing a high sensitivity of 249 nm/RIU and high resolution, with a figure of merit of 1132, at the resonant wavelength of 373 nm.
The First Residue of the PWWP Motif Modulates HATH Domain Binding, Stability, and Protein-Protein Interaction
(2015-07-07)
Hung, Yi-Lin
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Lee, Hsia-Ju
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Jiang, Ingjye
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Lin, Shang-Chi
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Lo, Wei-Cheng
Hepatoma-derived growth factor (hHDGF) and HDGF-related proteins (HRPs) contain conserved N-terminal HATH domains with a characteristic structural motif; namely the PWWP motif. The HATH domain has attracted attention because of its ability to bind with heparin/heparan sulfate, DNA, and methylated histone peptide. Depending on the sequence of the PWWP motif, HRP HATHs are classified into P-type (Pro-His-Trp-Pro) and A-type (Ala-His-Trp-Pro) forms. A-type HATH is highly unstable and tends to precipitate in solution. We replaced the Pro residue in P-type HATH(HDGF) with Ala and evaluated the influence on structure, dynamics, and ligand binding. Nuclear magnetic resonance (NMR) hydrogen/deuterium exchange and circular dichroism (CD) measurements revealed reduced stability. Analysis of NMR backbone N-15 relaxations (R-1, R-2, and nuclear Overhauser effect) revealed additional backbone dynamics in the interface between the beta-barrel and the C-terminal helix bundle. The beta 1-beta 2 loop, where the AHWP sequence is located, has great structural flexibility, which aids HATH-HATH interaction through the loop. A-type HATH, therefore, shows a stronger tendency to aggregate when binding with heparin and DNA oligomers. This study defines the role of the first residue of the PWWP motif in modulating HATH domain stability and oligomer formation in binding.