Besides being a common threat to farm animals and poultry, coronavirus (CoV) was responsible for the human severe acute respiratory syndrome (SARS) epidemic in 2002–4. However, many aspects of CoV behavior, including modes of its transmission, are yet to be fully understood. We show that the amount and the peculiarities of distribution of the protein intrinsic disorder in the viral shell can be used for the efficient analysis of the behavior and transmission modes of CoV. The proposed model allows categorization of the various CoVs by the peculiarities of disorder distribution in their membrane (M) and nucleocapsid (N). This categorization enables quick identification of viruses with similar behaviors in transmission, regardless of genetic proximity. Based on this analysis, an empirical model for predicting the viral transmission behavior is developed. This model is able to explain some behavioral aspects of important coronaviruses that previously were not fully understood. The new predictor can be a useful tool for better epidemiological, clinical, and structural understanding of behavior of both newly emerging viruses and viruses that have been known for a long time. A potentially new vaccine strategy could involve searches for viral strains that are characterized by the evolutionary misfit between the peculiarities of the disorder distribution in their shells and their behavior. 1. Introduction 1.1. Protein Intrinsic Disorder and Viral Behavior Previously, we provided evidence that the behavior of viruses can be predicted from the analysis of their predicted intrinsic disorder in their protein shells, more specifically, by looking at the peculiarities of disorder distribution in their matrix and capsid proteins [1–3]. For example, the predicted disorder in the matrix of retroviruses was shown to vary with the mode of the viral transmission. The HIV and EIAV viruses, that are related but have distinctly different modes of transmission, were used to illustrate this point since. HIV is largely transmitted sexually, whereas EIAV is transmitted by a blood-sucking horsefly. It has been observed that the abundance of predicted intrinsic disorder (PID) in the HIV and EIAV matrix proteins was very different, with the HIV proteins being highly disordered, especially HIV-1. An explanation for this has to do with the need for a more rigid encasement in viruses that are not sexually transmitted, so as to protect the virion from harsher environmental factors [1]. 1.2. Goals Further development of a model that could predict how a virus will behave in terms of
References
[1]
G. K. M. Goh, V. N. Uversky, and A. K. Dunker, “A comparative analysis of viral matrix proteins using disorder predictors,” Virology Journal, vol. 5, article 126, 2008.
[2]
G. K. M. Goh, A. K. Dunker, and V. N. Uversky, “Protein intrinsic disorder toolbox for comparative analysis of viral proteins,” BMC Genomics, vol. 9, no. 2, article S4, 2008.
[3]
B. Xue, R. W. Williams, C. J. Oldfield, G. K. M. Goh, A. K. Dunker, and V. N. Uversky, “Viral disorder or disordered viruses: Do viral proteins possess unique features?” Protein and Peptide Letters, vol. 17, no. 8, pp. 932–951, 2010.
[4]
K. V. Holmes, “SARS coronavirus: a new challenge for prevention and therapy,” Journal of Clinical Investigation, vol. 111, no. 11, pp. 1605–1609, 2003.
[5]
K. Stadler, V. Masignani, M. Eickmann et al., “SARS—beginning to understand a new virus,” Nature Reviews Microbiology, vol. 1, no. 3, pp. 209–218, 2003.
[6]
I. T. S. Yu and J. J. Y. Sung, “The epidemiology of the outbreak of severe acute respiratory syndrome (SARS) in Hong Kong—What we do know and what we don't,” Epidemiology and Infection, vol. 132, no. 5, pp. 781–786, 2004.
[7]
I. M. Yu, M. L. Oldham, J. Zhang, and J. Chen, “Crystal structure of the severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein dimerization domain reveals evolutionary linkage between Corona- and Arteriviridae,” Journal of Biological Chemistry, vol. 281, no. 25, pp. 17134–17139, 2006.
[8]
H. Jayaram, H. Fan, B. R. Bowman et al., “X-ray structures of the N- and C-terminal domains of a coronavirus nucleocapsid protein: implications for nucleocapsid formation,” Journal of Virology, vol. 80, no. 13, pp. 6612–6620, 2006.
[9]
J. S. M. Peiris, C. M. Chu, V. C. C. Cheng et al., “Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study,” The Lancet, vol. 361, no. 9371, pp. 1767–1772, 2003.
[10]
L. J. Saif and K. Sestak, “Transgastroenteritis and porcine respiratory coronaviruses,” in Diseases of Swine, B. E. Straw and D. J. Taylor, Eds., chapter 30, pp. 489–508, Blackwell, 9th edition, 2006.
[11]
T. Abraham, Twenty-First Century Plague: The Story of SARS, Hong Kong University Press, 2004.
[12]
D. A. Groneberg, R. Hilgenfeld, and P. Zabel, “Molecular mechanisms of severe acute respiratory syndrome (SARS),” Respiratory Research, vol. 6, article 8, 2005.
[13]
M. D. Christian, S. M. Poutanen, M. R. Loutfy, M. P. Muller, and D. E. Low, “Severe acute respiratory syndrome,” Clinical Infectious Diseases, vol. 38, no. 10, pp. 1420–1427, 2004.
[14]
J. Wu, F. Xu, W. Zhou et al., “Risk factors for SARS among persons without Known Contact with SARS patients, Beijing, China,” Emerging Infectious Diseases, vol. 10, no. 2, pp. 210–216, 2004.
[15]
R. Atmar, “Coronaviruses,” in OSki's Pediatrics: Principle and Practice, J. A. McMillan, R. D. Feigin, C. DeAngelis, and M. D. Jones, Eds., pp. 1206–1208, 4 edition, 2006.
[16]
N. Acheson, Fundamental of Molecular Virology, Wiley, 2007.
[17]
M. B. Pensaert and S. Yeo, “Porcine epidemic diarrhea,” in Diseases of Swine, B. E. Straw and D. J. Taylor, Eds., chapter 22, pp. 367–372, Blackwell, 9 edition, 2006.
[18]
K. Sestak and L. J. Saif, “Porcine coronaviruses,” in Trends in Emerging Viral Infections of Swine, A. M. Gonzales, A. Monila, K. Yoon, and J. J. Zimmerman, Eds., Section 10.1, p. 321, Iowa State Press, 2002.
[19]
C. C. Kao, P. Ni, M. Hema, X. Huang, and B. Dragnea, “The coat protein leads the way: an update on basic and applied studies with the Brome mosaic virus coat protein,” Molecular Plant Pathology, vol. 12, no. 4, pp. 403–412, 2011.
[20]
L. S. Ehrlich, T. Liu, S. Scarlata, B. Chu, and C. A. Carter, “HIV-1 capsid protein forms spherical (immature-like) and tubular (mature-like) particles in vitro: structure switching by pH-induced conformational changes,” Biophysical Journal, vol. 81, no. 1, pp. 586–594, 2001.
[21]
J. K. Cook, “Coronaviruses,” in Poultry Diseases, M. Pattison, J. McMullin, and J. Bradbury, Eds., pp. 340–349, 6 edition, 2008.
[22]
P. E. Wright and H. J. Dyson, “Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm,” Journal of Molecular Biology, vol. 293, no. 2, pp. 321–331, 1999.
[23]
P. H. Weinreb, W. Zhen, A. W. Poon, K. A. Conway, and P. T. Lansbury, “NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded,” Biochemistry, vol. 35, no. 43, pp. 13709–13715, 1996.
[24]
V. N. Uversky, J. R. Gillespie, and A. L. Fink, “Why are “natively unfolded” proteins unstructured under physiologic conditions?” Proteins: Structure, Function and Genetics, vol. 41, no. 3, pp. 415–427, 2000.
[25]
V. N. Uversky and A. K. Dunker, “Understanding protein non-folding,” Biochimica et Biophysica Acta, vol. 1804, no. 6, pp. 1231–1264, 2010.
[26]
A. K. Dunker, J. D. Lawson, C. J. Brown et al., “Intrinsically disordered protein,” Journal of Molecular Graphics and Modelling, vol. 19, no. 1, pp. 26–59, 2001.
[27]
V. Vacic, V. N. Uversky, A. K. Dunker, and S. Lonardi, “Composition Profiler: a tool for discovery and visualization of amino acid composition differences,” BMC Bioinformatics, vol. 8, article 211, 2007.
[28]
P. Radivojac, L. M. Iakoucheva, C. J. Oldfield, Z. Obradovic, V. N. Uversky, and A. K. Dunker, “Intrinsic disorder and functional proteomics,” Biophysical Journal, vol. 92, no. 5, pp. 1439–1456, 2007.
[29]
R. M. Williams, Z. Obradovi, V. Mathura et al., “The protein non-folding problem: amino acid determinants of intrinsic order and disorder,” Pacific Symposium on Biocomputing, pp. 89–100, 2001.
[30]
P. Romero, Z. Obradovic, X. Li, E. C. Garner, C. J. Brown, and A. K. Dunker, “Sequence complexity of disordered protein,” Proteins, vol. 42, pp. 38–48, 2001.
[31]
A. K. Dunker, J. D. Lawson, C. J. Brown et al., “Intrinsically disordered protein,” Journal of Molecular Graphics and Modelling, vol. 19, no. 1, pp. 26–59, 2001.
[32]
B. He, K. Wang, Y. Liu, B. Xue, V. N. Uversky, and A. K. Dunker, “Predicting intrinsic disorder in proteins: an overview,” Cell Research, vol. 19, no. 8, pp. 929–949, 2009.
[33]
S. Vucetic, C. J. Brown, A. K. Dunker, and Z. Obradovic, “Flavors of protein disorder,” Proteins, vol. 52, no. 4, pp. 573–584, 2003.
[34]
P. Romero, Z. Obradovic, C. R. Kissinger et al., “Thousands of proteins likely to have long disordered regions,” Pacific Symposium on Biocomputing, pp. 437–448, 1998.
[35]
E. Garner, P. Romero, A. K. Dunker, C. Brown, and Z. Obradovic, “Predicting binding regions within disordered proteins,” Genome Informatics, vol. 10, pp. 41–50, 1999.
[36]
Z. Obradovic, K. Peng, S. Vucetic, P. Radivojac, C. J. Brown, and A. K. Dunker, “Predicting intrinsic disorder from amino acid sequence,” Proteins, vol. 53, no. 6, pp. 566–572, 2003.
[37]
A. S. Perelson, J. G. Bragg, and F. W. Wiegel, “The complexity of the immune system: scaling laws,” in Complex Systems Science in Biomedicine, pp. 451–459, 2006.
[38]
G. K. M. Goh, A. K. Dunker, and V. N. Uversky, “Protein intrinsic disorder and influenza virulence: the 1918 H1N1 and H5N1 viruses,” Virology Journal, vol. 6, article 69, 2009.
[39]
J. Ignjatovi？ and S. Sapats, “Avian infectious bronchitis virus,” OIE Revue Scientifique et Technique, vol. 19, no. 2, pp. 493–508, 2000.
[40]
F. Esper, C. Weibel, D. Ferguson, M. L. Landry, and J. S. Kahn, “Coronavirus HKU1 infection in the United States,” Emerging Infectious Diseases, vol. 12, no. 5, pp. 775–779, 2006.
[41]
F. Esper, Z. Ou, and Y. T. Huang, “Human coronaviruses are uncommon in patients with gastrointestinal illness,” Journal of Clinical Virology, vol. 48, no. 2, pp. 131–133, 2010.
[42]
W. Smith, “The action of bile salts on viruses,” The Journal of Pathology and Bacteriology, vol. 48, pp. 557–571, 2005.
[43]
I. T. S. Yu, Y. Li, T. W. Wong et al., “Evidence of airborne transmission of the severe acute respiratory syndrome virus,” New England Journal of Medicine, vol. 350, no. 17, pp. 1731–1739, 2004.
[44]
J. Wu, F. Xu, W. Zhou et al., “Risk factors for SARS among persons without known contact with SARS patients, Beijing, China,” Emerging Infectious Diseases, vol. 10, no. 2, pp. 210–216, 2004.
[45]
A. Herráez, “Biomolecules in the computer: jmol to the rescue,” Biochemistry and Molecular Biology Education, vol. 34, no. 4, pp. 255–261, 2006.
[46]
R. Apweiler, A. Bairoch, C. H. Wu et al., “UniProt: the universal protein knowledgebase,” Nucleic Acids Research, vol. 32, pp. D115–D119, 2004.
