Skip to main content

Advertisement

SpringerLink
Log in

Incorporating the amino acid properties to predict the significance of missense mutations

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Determining if missense mutations are deleterious is critical for the analysis of genes implicated in disease. However, the mutational effects of many missense mutations in databases like the Breast Cancer Information Core are unclassified. Several approaches have emerged recently to determine such mutational effects but none have utilized amino acid property indices. We modified a previously described phylogenetic approach by first classifying benign substitutions based on the assumption that missense mutations that are maintained in orthologs are unlikely to affect function. A consensus conservation score based on 16 amino acid properties was used to characterize the remaining substitutions. This approach was evaluated with experimentally verified T4 lysozyme missnese mutations and is shown to be able to sieve out putative biochemical and structurally important residues. The use of amino acid properties can enhance the prediction of biochemical and structurally important residues and thus also predict the significance of missense mutations.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Alber T, Sun DP, Wilson K, Wozniak JA, Cook SP, Matthews BW (1987) Contributions of hydrogen bonds of Thr 157 to the thermodynamic stability of phage T4 lysozyme. Nature 330:41–46

    Article  PubMed  CAS  Google Scholar 

  • Barker DF, Almeida ER, Casey G, Fain PR, Liao SY, Masunaka I, Noble B, Kurosaki T, Anton-Culver H (1996) BRCA1 R841W: a strong candidate for a common mutation with moderate phenotype. Genet Epidemiol 13:595–604

    Article  PubMed  CAS  Google Scholar 

  • Beroud C, Soussi T (1998) p53 gene mutation: software and database. Nucleic Acids Res 26:200–204

    Article  PubMed  CAS  Google Scholar 

  • Cai Z, Tsung EF, Marinescu VD, Ramoni MF, Riva A, Kohane IS (2004) Bayesian approach to discovering pathogenic SNPs in conserved protein domains. Hum Mutat 24:178–184

    Article  PubMed  CAS  Google Scholar 

  • Charton M, Charton BI (1983) The dependence of the Chou–Fasman parameters on amino acid side chain structure. J Theor Biol 102:121–134

    Article  PubMed  CAS  Google Scholar 

  • Chasman D, Adams RM (2001) Predicting the functional consequences of non-synonymous single nucleotide polymorphisms: structure-based assessment of amino acid variation. J Mol Biol 307:683–706

    Article  PubMed  CAS  Google Scholar 

  • Chou KC (1993) A vectorized sequence-coupling model for predicting HIV protease cleavage sites in proteins. J Biol Chem 268:16938–16948

    PubMed  CAS  Google Scholar 

  • Chou KC (1996) Prediction of human immunodeficiency virus protease cleavage sites in proteins. Anal Biochem 233:1–14

    Article  PubMed  CAS  Google Scholar 

  • Chou KC (2004) Structural bioinformatics and its impact to biomedical science. Curr Med Chem 11:2105–2134

    PubMed  CAS  Google Scholar 

  • Chou KC (2006) Structural bioinformatics and its impact to biomedical science and drug discovery. In: Atta-ur-Rahman, Reitz AB (eds) Frontiers in medicinal chemistry, vol 3. Bentham Science Publishers, Bussum, The Netherlands, pp 455–502

  • Chou KC, Wei DQ, Du QS, Sirois S, Zhong WZ (2006) Progress in computational approach to drug development against SARS. Curr Med Chem 13:3263–3270

    Article  PubMed  CAS  Google Scholar 

  • Chou KC, Wei DQ, Zhong WZ (2003) Binding mechanism of coronavirus main proteinase with ligands and its implication to drug design against SARS. Biochem Biophys Res Commun 308:148–151

    Article  PubMed  CAS  Google Scholar 

  • Chou PY, Fasman GD (1978) Prediction of the secondary structure of proteins from their amino acid sequence. Adv Enzymol Relat Areas Mol Biol 47:45–148

    PubMed  CAS  Google Scholar 

  • Dong J, Chang-Claude J, Wu Y, Schumacher V, Debatin I, Tonin P, Royer-Pokora B (1998) A high proportion of mutations in the BRCA1 gene in German breast/ovarian cancer families with clustering of mutations in the 3′ third of the gene. Hum Genet 103:154–161

    Article  PubMed  CAS  Google Scholar 

  • Du Q, Wang S, Wei D, Sirois S, Chou KC (2005a) Molecular modeling and chemical modification for finding peptide inhibitor against severe acute respiratory syndrome coronavirus main proteinase. Anal Biochem 337:262–270

    Article  PubMed  CAS  Google Scholar 

  • Du QS, Wang SQ, Chou KC (2007) Analogue inhibitors by modifying oseltamivir based on the crystal neuraminidase structure for treating drug-resistant H5N1 virus. Biochem Biophys Res Commun 362:525–531

    Article  PubMed  CAS  Google Scholar 

  • Du QS, Wang SQ, Jiang ZQ, Gao WN, Li Y, Wei DQ, Chou KC (2005b) Application of bioinformatics in search for cleavable peptides of SARSCoV Mpro and chemical modification of octapeptides. Med Chem 1:209–213

    Article  PubMed  CAS  Google Scholar 

  • Du QS, Wang SQ, Zhu Y, Wei DQ, Guo H, Sirois S, Chou KC (2004) Polyprotein cleavage mechanism of SARS CoV Mpro and chemical modification of the octapeptide. Peptides 25:1857–1864

    Article  PubMed  CAS  Google Scholar 

  • Durocher F, Shattuck-Eidens D, McClure M, Labrie F, Skolnick MH, Goldgar DE, Simard J (1996) Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations. Hum Mol Genet 5:835–842

    Article  PubMed  CAS  Google Scholar 

  • Fasman GD (1976). Handbook of biochemistry and molecular biology. CRC, Cleveland

    Google Scholar 

  • Fauchere JL, Charton M, Kier LB, Verloop A, Pliska V (1988) Amino acid side chain parameters for correlation studies in biology and pharmacology. Int J Pept Protein Res 32:269–278

    PubMed  CAS  Google Scholar 

  • Fleming MA, Potter JD, Ramirez CJ, Ostrander GK, Ostrander EA (2003) Understanding missense mutations in the BRCA1 gene: an evolutionary approach. Proc Natl Acad Sci USA 100:1151–1156

    Article  PubMed  CAS  Google Scholar 

  • Gao WN, Wei DQ, Li Y, Gao H, Xu WR, Li AX, Chou KC (2007) Agaritine and its derivatives are potential inhibitors against HIV proteases. Med Chem 3:221–226

    Article  PubMed  CAS  Google Scholar 

  • Goto NK, Skrynnikov NR, Dahlquist FW, Kay LE (2001) What is the average conformation of bacteriophage T4 lysozyme in solution? A domain orientation study using dipolar couplings measured by solution NMR. J Mol Biol 308:745–764

    Article  PubMed  CAS  Google Scholar 

  • Grantham R (1974) Amino acid difference formula to help explain protein evolution. Science 185:862–864

    Article  PubMed  CAS  Google Scholar 

  • Grutter MG, Gray TM, Weaver LH, Wilson TA, Matthews BW (1987) Structural studies of mutants of the lysozyme of bacteriophage T4. The temperature-sensitive mutant protein Thr157-Ile. J Mol Biol 197:315–329

    Article  PubMed  CAS  Google Scholar 

  • Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723

    Article  PubMed  CAS  Google Scholar 

  • Herrgard S, Cammer SA, Hoffman BT, Knutson S, Gallina M, Speir JA, Fetrow JS, Baxter SM (2003) Prediction of deleterious functional effects of amino acid mutations using a library of structure-based function descriptors. Proteins 53:806–816

    Article  PubMed  CAS  Google Scholar 

  • Jeanmougin F, Thompson JD, Gouy M, Higgins DG, Gibson TJ (1998) Multiple sequence alignment with Clustal X. Trends Biochem Sci 23:403–405

    Article  PubMed  CAS  Google Scholar 

  • Johnson MM, Houck J, Chen C (2005) Screening for deleterious nonsynonymous single-nucleotide polymorphisms in genes involved in steroid hormone metabolism and response. Cancer Epidemiol Biomarkers Prev 14:1326–1329

    Article  PubMed  CAS  Google Scholar 

  • Kawashima S, Ogata H, Kanehisa M (1999) AAindex: amino acid index database. Nucleic Acids Res 27:368–369

    Article  PubMed  CAS  Google Scholar 

  • Kidera A, Konishi Y, Oka M, Ooi T, Scheraga HA (1985a) Statistical analysis of the physical properties of the 20 naturally occurring amino acids. J Protein Chem 4:23–55

    Article  CAS  Google Scholar 

  • Kidera A, Konishi Y, Ooi T, Scheraga HA (1985b) Relation between sequence similarity and structural similarity in proteins. Role of important properties of amino acids. J Protein Chem 4:265–297

    Article  CAS  Google Scholar 

  • Klein P, Kanehisa M, DeLisi C (1984) Prediction of protein function from sequence properties. Discriminant analysis of a data base. Biochim Biophys Acta 787:221–226

    PubMed  CAS  Google Scholar 

  • Kondrashov AS, Sunyaev S, Kondrashov FA (2002) Dobzhansky–Muller incompatibilities in protein evolution. Proc Natl Acad Sci USA 99:14878–14883

    Article  PubMed  CAS  Google Scholar 

  • Krishnan VG, Westhead DR (2003) A comparative study of machine-learning methods to predict the effects of single nucleotide polymorphisms on protein function. Bioinformatics 19:2199–2209

    Article  PubMed  CAS  Google Scholar 

  • Kuhn LA, Swanson CA, Pique ME, Tainer JA, Getzoff ED (1995) Atomic and residue hydrophilicity in the context of folded protein structures. Proteins 23:536–547

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Hedges SB (1998) A molecular timescale for vertebrate evolution. Nature 392:917–920

    Article  PubMed  CAS  Google Scholar 

  • Kuroki R, Weaver LH, Matthews BW (1993) A covalent enzyme-substrate intermediate with saccharide distortion in a mutant T4 lysozyme. Science 262:2030–2033

    Article  PubMed  CAS  Google Scholar 

  • Kuroki R, Weaver LH, Matthews BW (1999) Structural basis of the conversion of T4 lysozyme into a transglycosidase by reengineering the active site. Proc Natl Acad Sci USA 96:8949–8954

    Article  PubMed  CAS  Google Scholar 

  • Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132

    Article  PubMed  CAS  Google Scholar 

  • Lau AY, Chasman DI (2004) Functional classification of proteins and protein variants. Proc Natl Acad Sci USA 101:6576–6581

    Article  PubMed  CAS  Google Scholar 

  • Li L, Wei DQ, Wang JF, Chou KC (2007a) Computational studies of the binding mechanism of calmodulin with chrysin. Biochem Biophys Res Commun 358:1102–1107

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Wei DQ, Gao WN, Gao H, Liu BN, Huang CJ, Xu WR, Liu DK, Chen HF, Chou KC (2007b) Computational approach to drug design for oxazolidinones as antibacterial agents. Med Chem 3:576–582

    Article  PubMed  CAS  Google Scholar 

  • Matsumura M, Wozniak JA, Sun DP, Matthews BW (1989) Structural studies of mutants of T4 lysozyme that alter hydrophobic stabilization. J Biol Chem 264:16059–16066

    PubMed  CAS  Google Scholar 

  • Matthews BW (1996) Structural and genetic analysis of the folding and function of T4 lysozyme. Faseb J 10:35–41

    PubMed  CAS  Google Scholar 

  • Mirkovic N, Marti-Renom MA, Weber BL, Sali A, Monteiro AN (2004) Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition. Cancer Res 64:3790–3797

    Article  PubMed  CAS  Google Scholar 

  • Mooney SD, Altman RB (2003) MutDB: annotating human variation with functionally relevant data. Bioinformatics 19:1858–1860

    Article  PubMed  CAS  Google Scholar 

  • Ng PC, Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Res 11:863–874

    Article  PubMed  CAS  Google Scholar 

  • Ng PC, Henikoff S (2002) Accounting for human polymorphisms predicted to affect protein function. Genome Res 12:436–446

    Article  PubMed  CAS  Google Scholar 

  • Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814

    Article  PubMed  CAS  Google Scholar 

  • Ochman H, Elwyn S, Moran NA (1999) Calibrating bacterial evolution. Proc Natl Acad Sci USA 96:12638–12643

    Article  PubMed  CAS  Google Scholar 

  • Petersen GM, Parmigiani G, Thomas D (1998) Missense mutations in disease genes: a Bayesian approach to evaluate causality. Am J Hum Genet 62:1516–1524

    Article  PubMed  CAS  Google Scholar 

  • Radzicka A, Pedersen L, Wolfenden R (1988) Influences of solvent water on protein folding: free energies of solvation of cis and trans peptides are nearly identical. Biochemistry 27:4538–4541

    Article  PubMed  CAS  Google Scholar 

  • Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900

    Article  PubMed  CAS  Google Scholar 

  • Rennell D, Bouvier SE, Hardy LW, Poteete AR (1991) Systematic mutation of bacteriophage T4 lysozyme. J Mol Biol 222:67–88

    Article  PubMed  CAS  Google Scholar 

  • Sanderson MJ (2003) r8s: inferring absolute rates of molecular evolution and divergence times in the absence of a molecular clock. Bioinformatics 19:301–302

    Article  PubMed  CAS  Google Scholar 

  • Santibanez Koref MF, Gangeswaran R, Santibanez Koref IP, Shanahan N, Hancock JM (2003) A phylogenetic approach to assessing the significance of missense mutations in disease genes. Hum Mutat 22:51–58

    Article  PubMed  CAS  Google Scholar 

  • Sneath PH (1966) Relations between chemical structure and biological activity in peptides. J Theor Biol 12:157–195

    Article  PubMed  CAS  Google Scholar 

  • Sunyaev SR, Eisenhaber F, Rodchenkov IV, Eisenhaber B, Tumanyan VG, Kuznetsov EN (1999) PSIC: profile extraction from sequence alignments with position-specific counts of independent observations. Protein Eng 12:387–394

    Article  PubMed  CAS  Google Scholar 

  • Szabo C, Masiello A, Ryan JF, Brody LC (2000) The breast cancer information core: database design, structure, and scope. Hum Mutat 16:123–131

    Article  PubMed  CAS  Google Scholar 

  • Tchernitchko D, Goossens M, Wajcman H (2004) In silico prediction of the deleterious effect of a mutation: proceed with caution in clinical genetics. Clin Chem 50:1974–1978

    Article  PubMed  CAS  Google Scholar 

  • Verzilli CJ, Stallard N, Whittaker JC (2005) Bayesian modelling of multivariate quantitative traits using seemingly unrelated regressions. Genet Epidemiol 28:313–325

    Article  PubMed  Google Scholar 

  • Wang JF, Wei DQ, Li L, Zheng SY, Li YX, Chou KC (2007a) 3D structure modeling of cytochrome P450 2C19 and its implication for personalized drug design. Biochem Biophys Res Commun 355:513–519

    Article  PubMed  CAS  Google Scholar 

  • Wang JF, Wei DQ, Lin Y, Wang YH, Du HL, Li YX, Chou KC (2007b) Insights from modeling the 3D structure of NAD(P)H-dependent D-xylose reductase of Pichia stipitis and its binding interactions with NAD and NADP. Biochem Biophys Res Commun 359:323–329

    Article  PubMed  CAS  Google Scholar 

  • Wang SQ, Du QS, Chou KC (2007c) Study of drug resistance of chicken influenza A virus (H5N1) from homology-modeled 3D structures of neuraminidases. Biochem Biophys Res Commun 354:634–640

    Article  PubMed  CAS  Google Scholar 

  • Wang SQ, Du QS, Zhao K, Li AX, Wei DQ, Chou KC (2007d) Virtual screening for finding natural inhibitor against cathepsin-L for SARS therapy. Amino Acids 33:129–135

    Article  PubMed  Google Scholar 

  • Weaver LH, Matthews BW (1987) Structure of bacteriophage T4 lysozyme refined at 1.7 A resolution. J Mol Biol 193:189–199

    Article  PubMed  CAS  Google Scholar 

  • Wei DQ, Du QS, Sun H, Chou KC (2006a) Insights from modeling the 3D structure of H5N1 influenza virus neuraminidase and its binding interactions with ligands. Biochem Biophys Res Commun 344:1048–1055

    Article  PubMed  CAS  Google Scholar 

  • Wei DQ, Sirois S, Du QS, Arias HR, Chou KC (2005) Theoretical studies of Alzheimer’s disease drug candidate 3-[(2,4-dimethoxy)benzylidene]-anabaseine (GTS-21) and its derivatives. Biochem Biophys Res Commun 338:1059–1064

    Article  PubMed  CAS  Google Scholar 

  • Wei DQ, Zhang R, Du QS, Gao WN, Li Y, Gao H, Wang SQ, Zhang X, Li AX, Sirois S, Chou KC (2006b) Anti-SARS drug screening by molecular docking. Amino Acids 31:73–80

    Article  PubMed  CAS  Google Scholar 

  • Wei H, Zhang R, Wang C, Zheng H, Li A, Chou KC, Wei DQ (2007) Molecular insights of SAH enzyme catalysis and implication for inhibitor design. J Theor Biol 244:692–702

    Article  PubMed  CAS  Google Scholar 

  • Williams RS, Glover JN (2003) Structural consequences of a cancer-causing BRCA1-BRCT missense mutation. J Biol Chem 278:2630–2635

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Yan S (2007) Prediction of mutations engineered by randomness in H5N1 hemagglutinins of influenza A virus. Amino Acids

  • Xiao X, Shao S, Ding Y, Huang Z, Chen X, Chou KC (2005) An application of gene comparative image for predicting the effect on replication ratio by HBV virus gene missense mutation. J Theor Biol 235:555–565

    Article  PubMed  CAS  Google Scholar 

  • Zhang R, Wei DQ, Du QS, Chou KC (2006) Molecular modeling studies of peptide drug candidates against SARS. Med Chem 2:309–314

    Article  PubMed  CAS  Google Scholar 

  • Zheng H, Wei DQ, Zhang R, Wang C, Wei H, Chou KC (2007) Screening for new agonists against Alzheimer’s disease. Med Chem 3:488–493

    Article  PubMed  CAS  Google Scholar 

  • Zimmerman JM, Eliezer N, Simha R (1968) The characterization of amino acid sequences in proteins by statistical methods. J Theor Biol 21:170–201

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the National Medical Research Council, Singapore and the Biomedical Research Council of A*STAR, Singapore.

Author information

Authors and Affiliations

  1. Bioinformatics Institute, 30 Biopolis Street, Singapore, 138671, Singapore

    Tze-Chuen Lee

  2. National Cancer Center, 11 Hospital Drive, Singapore, 169610, Singapore

    Ann S. G. Lee

  3. Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, 11221, Taiwan

    Kuo-Bin Li

Authors
  1. Tze-Chuen Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ann S. G. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kuo-Bin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kuo-Bin Li.

Additional information

T.-C. Lee and A. S. G. Lee contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, TC., Lee, A.S.G. & Li, KB. Incorporating the amino acid properties to predict the significance of missense mutations. Amino Acids 35, 615–626 (2008). https://doi.org/10.1007/s00726-008-0087-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-008-0087-9

Keywords

Search

Navigation