Skip to main content
Springer Nature Link
Log in

Molecular modeling in the age of clinical genomics, the enterprise of the next generation

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Protein modeling and molecular dynamics hold a unique toolset to aide in the characterization of clinical variants that may result in disease. Not only do these techniques offer the ability to study under characterized proteins, but they do this with the speed that is needed for time-sensitive clinical cases. In this paper we retrospectively study a clinical variant in the XIAP protein, C203Y, while addressing additional variants seen in patients with similar gastrointestinal phenotypes as the C203Y mutation. In agreement with the clinical tests performed on the C203Y patient, protein modeling and molecular dynamics suggest that direct interactions with RIPK2 and Caspase3 are altered by the C203Y mutation and subsequent loss of Zn coordination in the second BIR domain of XIAP. Interestingly, the variant does not appear to alter interactions with SMAC, resulting in further damage to the caspase and NOD2 pathways. To expand the computational strategy designed when studying XIAP, we have applied the molecular modeling tools to a list of 140 variants seen in CFTR associated with cystic fibrosis, and a list of undiagnosed variants in 17 different genes. This paper shows the exciting applications of molecular modeling in the classification and characterization of genetic variants identified in next generation sequencing.

XIAP in Caspase 3 and NOD2 signaling pathways

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2a–d
Fig. 3a–f
Fig. 4
Fig. 5a–d
Fig. 6a–c
Fig. 7a–c
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Ashkenazy H, Erez E, Martz E, Pupko T, Ben-Tal N (2010) ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids. Nucleic Acids Res 38:W529–W533

    Article  CAS  Google Scholar 

  2. Blom N, Gammeltoft S, Brunak S (1999) Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol 294:1351–1362

    Article  CAS  Google Scholar 

  3. Blom N, Sicheritz-Pontén T, Gupta R, Gammeltoft S, Brunak S (2004) Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics 4:1633–1649

    Article  CAS  Google Scholar 

  4. Chai JJ, Du CY, Wu JW, Kyin S, Wang XD, Shi YG (2000) Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 406:855–862

    Article  CAS  Google Scholar 

  5. Damgaard RB, Fiil BK, Speckmann C, Yabal M, zur Stadt U, Bekker-Jensen S, Jost PJ, Ehl S, Mailand N, Gyrd-Hansen M (2013) Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling. EMBO Mol Med 5:1278–1295

    Article  CAS  Google Scholar 

  6. Dinkel H, Michael S, Weatheritt RJ, Davey NE, Van Roey K, Altenberg B, Toedt G, Uyar B, Seiler M, Budd A et al (2012) ELM--the database of eukaryotic linear motifs. Nucleic Acids Res 40:D242–D251

    Article  CAS  Google Scholar 

  7. Di Domenico T, Walsh I, Martin AJM, Tosatto SCE (2012) MobiDB: a comprehensive database of intrinsic protein disorder annotations. Bioinforma Oxf Engl 28:2080–2081

    Article  Google Scholar 

  8. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, Yang R, Cieplak P, Luo R, Lee T et al (2003) A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem 24:1999–2012

    Article  CAS  Google Scholar 

  9. Eckelman BP, Salvesen GS, Scott FL (2006) Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 7:988–994

    Article  CAS  Google Scholar 

  10. Felsenstein J (1985) Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39:783

    Article  Google Scholar 

  11. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A et al (2011) COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 39:D945–D950

    Article  CAS  Google Scholar 

  12. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, Lin J, Minguez P, Bork P, von Mering C et al (2013) STRING v9.1: protein–protein interaction networks, with increased coverage and integration. Nucleic Acids Res 41:D808–D815

    Article  CAS  Google Scholar 

  13. Huang X, Wu Z, Mei Y, Wu M (2013) XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling. EMBO J 32:2204–2216

    Article  CAS  Google Scholar 

  14. Jacob HJ, Abrams K, Bick DP, Brodie K, Dimmock DP, Farrell M, Geurts J, Harris J, Helbling D, Joers BJ et al (2013) Genomics in clinical practice: lessons from the front lines. Sci Transl Med 5:194cm5

    Article  Google Scholar 

  15. Jones DT, Taylor WR, Thornton JM (1992) The rapid generation of mutation data matrices from protein sequences. Comput Appl Biosci CABIOS 8:275–282

    CAS  Google Scholar 

  16. Konagurthu AS, Whisstock JC, Stuckey PJ, Lesk AM (2006) MUSTANG: a multiple structural alignment algorithm. Proteins 64:559–574

    Article  CAS  Google Scholar 

  17. Krieg A, Correa RG, Garrison JB, Le Negrate G, Welsh K, Huang Z, Knoefel WT, Reed JC (2009) XIAP mediates NOD signaling via interaction with RIP2. Proc Natl Acad Sci USA 106:14524–14529

    Article  CAS  Google Scholar 

  18. Krieger E, Koraimann G, Vriend G (2002) Increasing the precision of comparative models with YASARA NOVA—a self-parameterizing force field. Proteins 47:393–402

    Article  CAS  Google Scholar 

  19. Krieger E, Joo K, Lee J, Lee J, Raman S, Thompson J, Tyka M, Baker D, Karplus K (2009) Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: four approaches that performed well in CASP8. Proteins 77(Suppl 9):114–122

    Article  CAS  Google Scholar 

  20. Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R et al (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–2948

    Article  CAS  Google Scholar 

  21. Lin Y-F, Lai T-C, Chang C-K, Chen C-L, Huang M-S, Yang C-J, Liu H-G, Dong J-J, Chou Y-A, Teng K-H et al (2013) Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies. J Clin Invest 123:3861–3875

    Article  CAS  Google Scholar 

  22. Liu Z, Cao J, Ma Q, Gao X, Ren J, Xue Y (2011) GPS-YNO2: computational prediction of tyrosine nitration sites in proteins. Mol Biosyst 7:1197–1204

    Article  CAS  Google Scholar 

  23. Mahadevan D, Chalasani P, Rensvold D, Kurtin S, Pretzinger C, Jolivet J, Ramanathan RK, Von Hoff DD, Weiss GJ (2013) Phase I trial of AEG35156 an antisense oligonucleotide to XIAP plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma. Am J Clin Oncol 36:239–243

    Article  CAS  Google Scholar 

  24. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791

    Article  CAS  Google Scholar 

  25. Muse SV, Gaut BS (1994) A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome. Mol Biol Evol 11:715–724

    CAS  Google Scholar 

  26. Prokop JW, Santos RAS, Milsted A (2013) Differential mechanisms of activation of the Ang peptide receptors AT1, AT2, and MAS: using in silico techniques to differentiate the three receptors. PLoS One 8:e65307

    Article  CAS  Google Scholar 

  27. Prokop JW, Petri V, Shimoyama ME, Watanabe IKM, Casarini DE, Leeper TC, Bilinovich SM, Jacob HJ, Santos RAS, Martins AS et al (2015) Structural libraries of protein models for multiple species to understand evolution of the renin-angiotensin system. Gen Comp Endocrinol 215:106–116

    Article  CAS  Google Scholar 

  28. Radivojac P, Vacic V, Haynes C, Cocklin RR, Mohan A, Heyen JW, Goebl MG, Iakoucheva LM (2010) Identification, analysis, and prediction of protein ubiquitination sites. Proteins 78:365–380

    Article  CAS  Google Scholar 

  29. Ren J, Wen L, Gao X, Jin C, Xue Y, Yao X (2008) CSS-Palm 2.0: an updated software for palmitoylation sites prediction. Protein Eng Des Sel PEDS 21:639–644

    Article  CAS  Google Scholar 

  30. Rigaud S, Fondanèche M-C, Lambert N, Pasquier B, Mateo V, Soulas P, Galicier L, Le Deist F, Rieux-Laucat F, Revy P et al (2006) XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444:110–114

    Article  CAS  Google Scholar 

  31. Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5:725–738

    Article  CAS  Google Scholar 

  32. Saleem M, Qadir MI, Perveen N, Ahmad B, Saleem U, Irshad T, Ahmad B (2013) Inhibitors of apoptotic proteins: new targets for anticancer therapy. Chem Biol Drug Des 82:243–251

    Article  CAS  Google Scholar 

  33. Shi YG (2002) Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell 9:459–470

    Article  CAS  Google Scholar 

  34. Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H, Remmert M, Söding J et al (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7:539

    Article  Google Scholar 

  35. Speckmann C, Ehl S (2014) XIAP deficiency is a mendelian cause of late-onset IBD. Gut 63:1031–1032

    Article  Google Scholar 

  36. Speckmann C, Lehmberg K, Albert MH, Damgaard RB, Fritsch M, Gyrd-Hansen M, Rensing-Ehl A, Vraetz T, Grimbacher B, Salzer U et al (2013) X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis. Clin Immunol Orlando Fla 149:133–141

    Article  CAS  Google Scholar 

  37. Tamura K, Nei M (1993) Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees. Mol Biol Evol 10:512–526

    CAS  Google Scholar 

  38. Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739

    Article  CAS  Google Scholar 

  39. Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G et al (2012) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337:64–69

    Article  CAS  Google Scholar 

  40. Trott O, Olson AJ (2010) AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461

    CAS  Google Scholar 

  41. Veillette A, Pérez-Quintero L-A, Latour S (2013) X-linked lymphoproliferative syndromes and related autosomal recessive disorders. Curr Opin Allergy Clin Immunol 13:614–622

    Article  CAS  Google Scholar 

  42. Worthey EA, Mayer AN, Syverson GD, Helbling D, Bonacci BB, Decker B, Serpe JM, Dasu T, Tschannen MR, Veith RL et al (2011) Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med Off J Am Coll Med Genet 13:255–262

    Google Scholar 

  43. Xu D, Zhang Y (2012) Ab initio protein structure assembly using continuous structure fragments and optimized knowledge-based force field. Proteins 80:1715–1735

    Article  CAS  Google Scholar 

  44. Xue Y, Liu Z, Gao X, Jin C, Wen L, Yao X, Ren J (2010) GPS-SNO: computational prediction of protein S-nitrosylation sites with a modified GPS algorithm. PLoS One 5:e11290

    Article  Google Scholar 

  45. Zhao Q, Xie Y, Zheng Y, Jiang S, Liu W, Mu W, Liu Z, Zhao Y, Xue Y, Ren J (2014) GPS-SUMO: a tool for the prediction of sumoylation sites and SUMO-interaction motifs. Nucleic Acids Res 42:W325–W330

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806, USA

    Jeremy W. Prokop, Jozef Lazar, D. Casey Smith, Elizabeth A. Worthey & Howard J. Jacob

  2. Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Jeremy W. Prokop, Jozef Lazar, Gabrielle Crapitto, Elizabeth A. Worthey & Howard J. Jacob

Authors
  1. Jeremy W. Prokop
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Jozef Lazar
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Gabrielle Crapitto
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. D. Casey Smith
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Elizabeth A. Worthey
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Howard J. Jacob
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Jeremy W. Prokop.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(ZIP 14635 kb)

ESM 2

(XLSX 42 kb)

ESM 3

(XLSX 22 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prokop, J.W., Lazar, J., Crapitto, G. et al. Molecular modeling in the age of clinical genomics, the enterprise of the next generation. J Mol Model 23, 75 (2017). https://doi.org/10.1007/s00894-017-3258-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-017-3258-3

Keywords