WCN  CELLO  CELLO2GO  (PS)2 v.2  (PS)2 v.3   

Jenn-Kang Hwang, PhD

Professor of Computational Biology

Executive Dean, Warshel Institute for Computational Biology, CUHKSZ (2017-2019)

Professor, National Chiao Tung University (2000-2017)

Vice President, Asia University (2014-2015)

Chair Professor, Department of Bioinformatics and Medical Engineering, Asia University (2014-2015)

Dean, College of Biological Science and Technology (2007 - 2013), NCTU

Director of the Center for Bioinformatics Research at NCTU

Associate Professor, National Tsing Hua University (1993-2000)


Academic Activities

President of Bioinformatics Society Taiwan

Member of Biophysics Society of R.O.C.

Editorial Board of Proteins: Structure, Function and Bioinformatics

Editorial Board of Biochemical Compounds

Editorial Board of the International Journal of Medical Engineering and Informatics



PhD, Dept Chem, USC. Thesis Advisor: Arieh Warshel (2013 Nobel Laureate

BSc, Dept Agr Chem, National Taiwan University, Taiwan, R.O.C.


E-mail: jkhwang [at] faculty [dot] nctu [dot] edu [dot] tw

Research Topics

We are interested in the structure-dynamics-evolution relationship in proteins. Protein's average thermal fluctuations are shown be derived directly from proten structures without assuming any mechanical models. A number of protein structural profiles such as residue packing, i.e. the weighted contact  number (WCN), protein centroid distance, thermal fluctuation profile or smoothed solvent accessible surface profiles are similar to a smoothed version of sequence conservation profile in varying degrees. 


This is surprising, since the WCN profile is derived from a single protein structure, while the sequence cpnservation profile is derived from multiple sequence alignment of a group of homologous sequences. This suggests that a single protein structure contains evolutionary information that was previously derived only from multiple sequences.


We are also interested in the following topics such as knotted proteins, protein subcellular localizationprotein structure predictiondisulfied proteins,molecular simulation and any topics that are intellectually interesting.




  1. Martin F et al. SBMOpenMM: A Builder of Structure-Based Models for OpenMM. J Chem. Inf. Mod. 61, 3166-3171 (2021)
  2. Lin CY et al. Membrane Protein-Regulated Networks across Human Cancers. Nature Communicationsvolume 10,  3131 (2019
  3. Liu JW et al. Relationships between residue Voronoi volume and sequence conservation in proteins BBA – Proteins and Proteomics (2018) 1866: 379-386
  4. Liu JW at al. On the Relationship between Residue Structural Environment and Sequence Conservation in Proteins Proteins. 2017 Jun 9. doi: 10.1002/prot.25329
  5. Liu KK et al. Ubiquitin-coated nanodiamonds bind to autophagy receptors for entry into the selective autophagy pathway. Autophagy 2017 Jan 2;13(1):187-200. doi: 10.1080/15548627.2016.1254864
  6. Chang CM et al. Sequence Conservation, Radial Distance and Packing Density in Spherical Viral Capsids, PLoS one 2015 DOI: 10.1371/journal.pone.0132234.    
  7. Huang TT et al. (PS)2: Protein Structure Prediction Server Version 3.0 Nucleic Acids Research 2015  43(W1):W338-42. doi: 10.1093/nar/gkv454.    
  8. Huang YW, Chang CM, Hwang JK The conservation profile of a protein bears the imprint of the molecule that is evolutionarily coupled to the protein Proteins  2015 83(8):1407-13. doi: 10.1002/prot.24809.
  9. JJ Lin, ZL Lin, JK Hwang, TT Huang On the packing density of the unbound protein-protein interaction interface and its implications in dynamics. BMC Bioinformatics 2015 16 (Suppl 1), S7.
  10. CW Lee, HJ Wang, JK Hwang, CP Tseng Protein Thermal Stability Enhancement by Designing Salt Bridges: A Combined Computational and Experimental Study PloS one 2014 9 (11), e112751
  11. Huang TT, del Valle Marcos ML, Hwang JK, Echave J. A mechanistic stress model of protein evolution accounts for site-specific evolutionary rates and their relationship with packing density and flexibility. J. BMC Evol Biol. 2014 Apr 9;14:78. doi: 10.1186/1471-2148-14-78.
  12. Yeh SW, Liu JW, Yu SH, Shih CH, Hwang JK, Echave J. Site-specific structural constraints on protein sequence evolutionary divergence: local packing density versus solvent exposure. Mol Biol Evol. 2014 Jan;31(1):135-9. doi: 10.1093/molbev/mst178.
  13. Yeh SW, Huang TT, Liu JW, Yu SH, Shih CH, Hwang JK, Echave J. Local packing density is the main structural determinant of the rate if protein sequence sequence at the site level. J. Biomed Res Int. 2014;2014:572409. doi: 10.1155/2014/572409.

  14. Yu CS, Cheng CW, Su WC, Chang KC, Huang SW, Hwang JK, Lu CH. CELLO2GO: a web server for protein subCELlular LOcalization prediction with functional gene ontology annotation. PLoS One. 2014  Jun 9; 9(6):e99368. doi: 10.1371/journal.pone.0099368  

  15. Lee CH, Chen YW, Huang YT, Pan YJ, Lee CH, Lin SM, Huang LK, Lo YY, Huang YF, Hsu YD, Yen SC, Hwang JK, Pan RL. Functional investigation of transmembrane helix 3 in H⁺-translocating pyrophosphatase. J Membr Biol. 2013 Dec; 246(12):959-66.
  16. **Chang CM, Huang YW, Shih CH, Hwang JK. On the relationship between the sequence conservation and the packing density profiles of the protein complexes. Proteins. 2013 Jul;81(7):1192-9. doi: 10.1002/prot.24268. 

    >> This paper applied the WCN method to the understanding of the evolutionary coulings between the subunits of an enzyme complex.
  17. Chen CC, Er TK, Liu YY, Hwang JK, Barrio MJ, Rodrigo M, Garcia-Toro E, Herreros-Villanueva M. Computational Analysis of KRAS mutations: Implications for different effects on the KRAS p.G12D and p.G13D mutations. Plos ONE 2013 . 2013;8(2):e55793. doi: 10.1371/journal.pone.0055793.
  18. Liu YY, Shih CH, Hwang JK, Chen CC. Deriving correlated motions in proteins from x-ray structure refinement using TLS parameters Gene 2013 Apr 10;518(1):52-8. doi: 10.1016/j. gene.2012.11.086.
  19. **Shih CH, Chang CM, Lin YS, Lo WC, Hwang JK. Evolutionary information hidden in a single protein structure. Proteins (2012) 80, 16472.

  20. Lai YL, Chen CC, Hwang JK. pKNOT v2.0: the protein KNOT web server. Nucleic Acids Research (2012) doi: 10.1093/nar/gks592
  21. Lo WC, Wang LF, Liu YY, Dai T, Hwang JK Lyu PC. CPred: a web server for predicting viable circular permutations in proteins. Nucleic Acids Research (2012) 10.1093/nar/gks529.
  22. Lo WC, Dai T, Liu YY, Wang LF, Hwang JK, PC Lyu. Deciphering the preference and predicting the viability of circular permutations in proteins. (2012) Plus One, 7, e31791.
  23. Chien YT, Hwang JK, Huang SW. On the relationship between residue solvent exposure and thermal fluctuations in proteins. Protein Structure (2012) ISBN 979-953-307-576-0.
  24. Er TK, Chen CC, Liu YY, Chang LC, Chien, YH, Chang JG, Hwang JK Jong YJ. Computational analysis of a novel mutation in ETFDH gene highlights in its long-range effects on the FAD-binding motif. BMC Structural Bioinformartics (2011) 11:43.
  25. *Huang SW, Yu SH, Shih CH, Guan HW, Huang TT, Hwang JK. On the relationship between catalytic residues and their protein contact number. Current Protein and Peptide Science (2011) 1;12(6):574-9

    >> A paper by Nosrati and Houk on prediction of catalytic function of enzymes was based on the WCN method.
  26. Chiang AS, Lin CY, Chuang CC, Chang HM, Hsieh CH, Yeh CW, Shih CT, Wu JJ, Wang GT, Chen YC, Wu CC, Chen GY, Ching YT, Lee PC, Lin CY, Lin HH, Wu CC, Hsu HW, Huang YA, Chen JY, Chiang HJ, Lu CF, Ni RF, Yeh CY, Hwang JK. Three-Dimensional Reconstruction of Brain-wide Wiring Networks in Drosophila at Single-Cell Resolution. Curr Biol. (2011) Jan 11;21(1):1-11.
  27. Huang SW, Hwang JK. Bioinformatics-Experimantal Biology Systems: On the Structural Characteristics of the Protein Active Sites and Their Relation to Thermal Fluctuations (2011). ISBN: ISBN 978-953-307-280-7.
  28. Chu CH, Lo WC, Wang HW, Hsu YC, Hwang JK, Lyu PC, TW Pai, CY Tang. Detection and alignment of 3D domain swapping proteins using angle-distance image-based secondary structural matching techniques. Plos One (2010) 14;5(10):e13361.
  29. *Lai et al. Comprehensive Analysis of Knotted Proteins in Sequence and Genome Analysis: Methods and Applications (2010). ISBN: 978-0-9807330-4-4 
  30. Chen CC, Hwang JK, Yang JM PS2-v2: template-based protein structure prediction server. BMC Bioinformatics (2009) 10, 366
  31. Huang SW, Shih CH, Lin CP, Hwang JK Prediction of NMR order parameters in proteins using weighted protein contact-number model. Theor Chem Acc (2008) 121, 197-200
  32. Cheng SW, Su ECY, Hwang JK, Sun TY, Hsu WL Predicting RNA-binding sites of proteins using support vector machines and evolutionary information. BMC Bioinformatics, (2008) 9, S6.
  33. **Lin CP, Huang SW, Lai YL, Yen SC, Shih CH, Lu CH, Huang CC, Hwang JK. Deriving protein dynamical properties from weighted protein contact number, Proteins: Structure, Function and Bioinformatics (2008) 72, 929-935.
    >> A recent Jernigans' PNAS paper on Elastic Nwtwork Model was based on WCN

  34. *Lu CH, Huang SW, Lai YL, Lin CP, Shih CH, Huang CC, Hsu WL, Hwang JK. On the relationship between the protein structure and protein dynamics, Proteins: Structure, Function and Bioinformatics (2008) 72, 625-634
  35. Shih CH, Huang SW, Yen SC, Lai YL, Yu SH, Hwang JK. Computation of protein dynamics without a mechanical model, Proteins: Structure, Function and Bioinformatics (2007) 68, 34-38
  36. Chiu, YY, Hwang JK, Yang JM, Soft energy function and generic evolutionary method for discriminating native from non-native protein conformations, J. Comp. Chem. (2008) 29, 1364-1373.
  37. Tsai YC, Lin YM, Hwang JK, Yu JSK, On the Stereochemistry of Zn-Zn Bonds: Synthesis, Structural Transformation, and Computations, Chem. Comm. (2007) 40:4125-4127 
  38. Su ECY, Chiu HS, Lo A, Hwang JK, TY Sung, WL Hsu, Protein subcellular localization prediction based on compartment-specific features and structure conservation, BMC Bioinformatics (2007) 8:330-341. 
  39. Lai YL, Yen SC, Yu SH, Hwang JK. pKNOT: the Protein KNOT web server, Nucleic Acids Research (2007) 35:W420-W424 ; [Go to: The pKNOT server]. 
  40. Wong YH, Lee TY, Liang HK, Huang CM, Yang YH, Chu CH, Huang HD, Ko MT, Hwang JK, KinasePhos 2.0: a web server for identifying protein kinase-specific phosphorylation sites based on sequences and coupling patterns, Nucleic Acids Research (2007) 35:W588-594.
  41. Huang CL, Liu JH, Chiu WC, Huang SW, Hwang JK, Wang WC. Crystal structure of Helicobacter pylori formamidase AmiF reveals a cysteine-glutamate-lysine catalytic triad. J. Biol. Chem. (2007) 282:12220-12229. 
  42. Lin YS, Hsu WL, Hwang JK, Li WH. Proportion of solvent-exposed amino acids in a protein and rate of protein evolution, Molecular Biology and Evolution (2007) 24, 1005-11. 
  43. Lu CH, Chen YC, Yu CS, Hwang JK. Predicting disulfide connectivity patterns, Proteins: Structure, Function and Bioinformatics (2007) 67: 262-270
  44. Tsai YC, Lin YM, Yu, JSK, Hwang JK. A three-coordinate and quaruply bonded Mo-Mo-Complex, J. Am. Chem. Soc. (2006) 128:13980-13981
  45. Lin YS, Byrnes JK, Hwang JK, Li WH. Codon usage bias versus gene conversion in the evolution of yeast duplicate genes. Proc. Natl. Acad. Sci. USA. (2006) 103:14412-1441628.
  46. Lin YS, Hwang JK, Li WH. Protein complexity, gene duplicability and gene dispensability in the yeast genome. Gene. (2006) [Epub ahead of print].
  47. *Yu CH, Chen YC, Lu CH, Hwang JK. Prediction of protein subcellular localization. Proteins: Structure, Function and Bioinformatics (2006),  387, 109-117.
  48. Chiu WC, You JY, Liu JS, Hsu SK, Hsu WH, Shih CH, Hwang JK, Wang WC, Structure-stability-activity relationship in covalently c 1 ross-linked N-carbamoyl D-amino acid amidohydrolase and N-acylamino acid racemase. J. Mol. Biol. (2006), 359: 741-753.
  49. Chen CC, Hwang JK, JM Yang. Protein structure prediction server. Nucleic Acids Research (2006), 34: W152-157.
  50. Lu CH, Lin SH, Chen YC, Yu CS, Chang SY, Hwang JK. The fragment transformation method to detect the protein structural motifs. Proteins: Structure, Function and Bioinformatics (2006), 63:636-643.
  51. Hung SW, Hwang JK, Tseng F, Chang JM Chen CC, Chieng CC. Molecular dynamics simulation on enhancement of CTX and E6 protein binding on mixed SAMs molecules. Nanotechnology (2006), 17, S8-13
  52. Chen YC, Hwang JK Prediction of disulfide connectivity from protein sequences. Proteins: Structure, Function and Bioinformatics (2005) 61, 507-512. 
  53. **Huang SW, Hwang JK. Computation of conformational entropy from protein sequences using the machine-learning method - Application to the study of the relationship between structural conservation and local structural stability. Proteins: Structure, Function and Bioinformatics (2005), 59, 802-809. 
  54. Liang HK, Huang CM, Ko MT, Hwang JK. The Amino Acid-Coupling Patterns in Thermophilic Proteins. Proteins: Structure, Function and Bioinformatics (2005), 59, 58-63. 
  55. Lin YS, Tzeng CS, Hwang JK. Reassessment of morphological characters in freshwater eels (genus Anguilla, Anguillidae) shows congruence with molecular phylogeny estimate. Zoologica Scripta (2005), 34, 225-234. 
  56. **Chan CH, Liang HK, Hsiao NW, Ko MT, Lyu PC, Hwang JK. The relationship between local structural entropy and protein thermostability. Proteins: Structure, Function and Bioinformatics (2004), 57, 684-691.

    >> Philips and co-works used our Local Structural Entropy method to successfully design thermally stable adenylated kinase (PNAS 2008).
  57. Chen YC, Lin YS, Lin CJ and Hwang JK. Prediction of the Bonding States of Cysteines using the Support Vector Machines Based on Multiple Feature Vectors and Cysteine State Sequences. Proteins: Structure, Function and Bioinformatics (2004), 55, 1046-42.
  58. *Yu CS, Lin CJ, Hwang JK, Predicting Subcellular Localization of Proteins For Gram-Negative Bacteria by Support Vector Machines Based on n-Peptide Compositions. Protein Science (2004), 13, 1402-1406 
  59. Yu JSK, Hwang JK, Tang CY, Yu CH. Numerical performance and throughput benchmark for electronic structure calculations in PC-Linux System with new architectures, updated compilers and library. J. Chem. Inf. Comput. Sci (2004), 44, 635-642. 
  60. Yu CS, Wang JY, Yang JM, Lyu PC, Lin CJ, Hwang JK, Fine-grained protein fold assignment by support vector machines using generalized n-peptide coding schemes and jury voting from multiple parameter sets. Proteins: Structure, Function, Genetics  (2003) 50,531-536 
  61. Horng JT, Huang HD, Wang SH, Chen MY, and Hwang JK, Computing   motif correlations in proteins. J. Comp. Chem. (2003), 24, 2032-2043. 
  62. **Chuang CC, Chen CY, Yang JM, Lyu PC, Hwang JK, Relationship between protein structures and disulfide-bonding patterns. Proteins: Structure, Function and Genetics (2003), 53, 1-5. 
  63. Chan CH, Lyu PC, Hwang JK, Computation of the Protein Structure Entropy and its Applications to Protein Folding Processes. J. Chin. Chem. Soc. (2003), 50, 677-684. 
  64. Yang JM, Tsai CH, Hwang MJ, Tsai HK, Hwang JK, Kao CY, GEM: A Gaussian evolutionary method for predicting protein side-chain conformations. Protein Sci. (2002), 11, 1897-1907. 
  65. **Hwang JK,The partial averaging Fourier path integral approach based on the harmonic reference path,  Theo. Chem. Acc. 101 (1999) 5, 359-363 
  66. Lin CH, Chan FCH, Hwang JK, Lyu PC, Calcium binding mode of -carboxyglutamic acids in Conantokins, Protein Engineering (1999) 12, 101-107 
  67. Fan ZZ,  Hwang JK, Warshel A, Using simplified protein representaion as a reference potential for all-atom calculations of folding free energy  Theo. Chem. Acc. (1999) 103, 77-80 
  68. Yang YS, Pan JJ,  Hwang JK, Probing phenol binding environment of sulfotransferase. Protein Engineering   10A, 70 (1997)
  69. Vyas A, Pan JJ, Patel HV, Vyas KA, Chiang CM, Sheu YC, Hwang JK, Wu WG, Analysis of binding of cobra cardiotoxins to heparin reveals a new beta-sheet heparin-binding structural motif. J. Biol. Chem. 272, 9661(1997)
  70. *Hwang JK, Warshel A, On the relationship between the dispersed polaron and spin-boson models. Chem. Phys. Lett. 271, 223 (1997).

    >> This paper showed that our dispersed polaron is essentially equivalent to the spin-boson models but has the advantahe of being easily applied to very large sysems.
  71. Chan FCH, Pan JJ, Fan ZZ, Hsieh FMJ, Hwang JK, Computer simulation of chemical reactions in biological systems, Chemistry, 55, 1 (1997)
  72. Pan JJ,  Hwang JK, Mixed Quantum Mechanical/Molecular Mechanical Simulations of Chemical Reactions in Solution and in Enzymes, in Pacific Symposium on Biocomputing '96 edited by Lawrence Hunter and Teri E. Klein. (World Scientific, Singapore, 1996) p.539-549
  73. Hwang JK,  Pan JJ, Classical Trajectory Mapping Approach for Simulations of Chemical Reactions in solution and in enzyme. J. Phys. Chem. 100, 909 (1996).
  74. Hwang JK, Warshel A, How important are quantum mechanical nuclear motions in enzyme catalysis. J. Am. Chem. Soc. 118, 11745 (1996)
  75. **Hwang JK, Liao WF, Side-chain Prediction by Neural Networks and Simulated Annealing Optimization. Prot. Eng. 8, 363-370 (1995)
    >> My first attemp in using machine learning method to predict side-chain orientations of proteins.
  76. Hwang JK, Pan JJ, Simulation of Chemical Reactions in Solution by a Combination of Classical and Quantum Mechanical Approach. Chem. Phys. Lett. 243, 171-175 (1995)
  77. Hwang JK, Chang CC, Computer Simulation of Enzymatic Reaction  Chemistry, 52, 246-250 (1994). 
  78. *Hwang JK, Warshel A, A Quantized Classical Path Approach for Calculations of Quantum Mechanical Rate Constants.  J.  Phys. Chem. 97, 10053-10058 (1993).
  79. Warshel A, Hwang JK, Åqvist J, Computer Simulations of Enzymatic reactions: Examination of Linear Free-Energy Relationships and Quantum-mechanical Corrections in the Initial Proton-Transfer Step of Carbonic Anhydrase.  Faraday Discuss. 93, 225-238 (1992).
  80. Hwang JK, Chu ZT, Yadav A, Warshel A, Simulations of Quantum Mechanical Corrections for Rate Constants of Hydride-transfer Reactions in Enzymes and Solutions. J. Phys. Chem. 95 8445(1991).
  81. Warshel A, Naray-Szabo G, Sussman F, Hwang JK, Perspectives in Biochemistry Vol II, edited by Hans Neurath, (American Chemical Society 1991), p. 115.
  82. Warshel A, Chu ZT, Hwang JK, The Dynamics of the Primary event in rhodopsins revisted. Chem. Phys. 158, 303 (1991)
  83. Warshel A, Naray-Szabo G, Sussman F, Hwang JK, How Do Serine Proteases Really Work? Biochemistry 28, 3629 (1989).
  84. Hwang JK, Calculation of quantum mechanical free energy at low temperature. Theo. Chem. Acc. 98, 202 (1998) 
  85. Hwang JK and Warshel A, Why Ion Pair Reversal by Protein Engineering is Unlikely to Succeed. Nature, 334,  270 (1988).
  86. Warshel A, Sussman F, Hwang JK, Evaluation of Catalytic Free Energies in Genetically Modified Proteins. J. Mol. Biol. 201, 139 (1988).
  87. Creighton S, Hwang JK, Warshel A, Parson WW, Norris J, Simulating The Dynamics of the Primary Charge Separation Process in Bacterial Photosynthesis. Biochemistry  27 774 (1988).
  88. Hwang JK,  Sussman F, and Warshel A, Simulating the Energetics and Dynamics of Enzymatic Reactions in Genetically Modified Enzymes in Structure and Expression, edited by R.H Sarma and M.H. Sarma (Adenine Press,New York 1988), p. 95.
  89. Hwang JK, Creighton S, King G, Whitney D, and Warshel A, Effects of Solute-Solvent Coupling and Solvent Saturation on Solvation Dynamics of Charge Transfer Reactions. J. Chem. Phys. 89, 859 (1988).
  90. Hwang JK, King G, Creighton S, Warshel A, Simulation of Free Energy Relationships and Dynamics of SN2 Reactions in Aqueous Solutions. J. Am. Chem. Soc. 110, 5297 (1988).
  91. Hwang JK,  Warshel A, Semiquantitative Calculations of Catalytic Free energies in Genetically Modified Subtilisin. Biochemistry, 26, 2669 (1987).
  92. Hwang JK, Warshel A, Microscopic Examination of Free-Energy Relationships for Electron Transfer in Polar Solvents. J. Am. Chem. Soc. 109, 715 (1987).
  93. Warshel A, Hwang JK, Simulation of the Dynamics of Electron Transfer Reactions in Polar Solvents: Semiclassical Trajectories and Dispersed Polaron Approaches. J. Chem. Phys. 84, 4938 (1986).
  94. Hwang JK, Warshel A, Semiclassical Simulation of the Spectra of Anharmonic Molecules: Problems and Alternatives. Chem. Phys. Lett. 115, 182 (1985).
  95. Hwang JK, Warshel A, A Shortcut for Multidimensional Quantization. The Average Partial Action Method. Chem. Phys. Lett. 118, 289 (1985).
  96. Warshel A, Hwang JK, Quantized Semiclassical Trajectory Approach for Evaluation of Vibronic Transitions in Anharmonic Molecules. J. Chem. Phys.1756, 82 (1985).
    >> My first paper with Arieh.
  97. Hwang JK, Yen GC, Hwang LS, Detection of Vegetable Oil Adulteration by HPLC Analysis of Triglycerides. J. Chin. Agric. Chem. Soc. 91, 20 (1982).
    >> My firts and only non-computational paper. It is food science paper.