Share This Article:

Gly→Ala Point Mutation and Conformation of Poly-Ala Stretch of PABPN1: A Molecular Dynamics Study

Abstract Full-Text HTML XML Download Download as PDF (Size:1197KB) PP. 54-63
DOI: 10.4236/jbpc.2015.62006    3,881 Downloads   4,380 Views  

ABSTRACT

Single nucleotide replacing mutations in genes cause a number of diseases, but sometimes these mutations mimic other genetic mutations such as trinucleotide repeats expansions. A mutation in codon GGG→GCG results in Gly→Ala at the N-terminal of PABPN1 protein that mimics the trinucleotide repeat expansion disease called Oculopharyngeal muscular dystrophy (OPMD). Molecular dynamics simulations in water with peptide models having sequence Ac-A10-GA2GG-NHme (peptide A) and Ac-A10A3GG-NHme (peptide B) reveal an increase in the length of helical segment in peptide B. The α-helical length is found to be stable in peptide B with starting geometry of a right handed helix, while in the case peptide A, the helical length is short. The interactions of water molecules at terminals, side chain-backbone interactions and hydrogen bonds provide stability to resultant conformation. The adopted helix by the poly-Ala stretch may lead to masking some other active parts of the PABPN1 that may trigger the aggregation, decrease in degradation and/or impaired function of protein. Hence, further studies with N-terminal may be helpful to understand unclear disease mechanism.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Shafique, M. , Garg, M. and Nandel, F. (2015) Gly→Ala Point Mutation and Conformation of Poly-Ala Stretch of PABPN1: A Molecular Dynamics Study. Journal of Biophysical Chemistry, 6, 54-63. doi: 10.4236/jbpc.2015.62006.

References

[1] Christopher, E.P., Edamura, K.N. and Cleary, J.D. (2005) Repeat Instability: Mechanisms of Dynamic Mutations. Nature Reviews Genetics, 6, 729-742.
http://dx.doi.org/10.1038/nrg1689
[2] Mirkin, S.M. (2007) Expandable DNA Repeats and Human Diseases. Nature, 447, 932-940.
http://dx.doi.org/10.1038/nature05977
[3] Brais, B., Bouchard, J.P., Xie, Y.G., Rochefort, D.L., Chretien, N., Tome, F.M., Lafrenier, R.G., Rommens, J.M., Uyama, E. and Nohira, O. (1998) Short GCG Expansions In The PABP2 Gene Cause Oculopharyngeal Muscular Dystrophy. Nature Genetics, 18, 164-166.
http://dx.doi.org/10.1038/ng0298-164
[4] Bao, Y., Cook, L.J., O’Donovan, D., Uyama, E. and Rubinsztein, D.C. (2002) Mammalian, Yeast, Bacterial and Hemical Chaperones Reduce Aggregate Formation and Death in a Cell Model of Oculopharyngeal Muscular Dystrophy. Journal of Biological Chemistry, 277, 12263-12269.
http://dx.doi.org/10.1074/jbc.M109633200
[5] Robinson, D.O., Wills, A.J., Hammans, S.R., Read, S.P. and Sillibourne, J. (2006) Oculopharyngeal Muscular Dystrophy: A Point Mutation Which Mimics the Effect of the Pabpn1 Gene Triplet Repeat Expansion Mutation. Journal of Medical Genetics, 43, e23-e24.
http://dx.doi.org/10.1136/jmg.2005.037598
[6] Robinson, D.O., Hilton-Jones, D., Mansfield, D., Hildebrand, R.D., Marks, S., Mechan, D. and Ramsay, J. (2011) Two Cases of Oculopharyngeal Muscular Dystrophy (OPMD) with the Rare PABPN1 C.35g > C; P.Gly12ala Point Mutation. Neuromuscular Disorders, 21, 809-811.
http://dx.doi.org/10.1016/j.nmd.2011.06.003
[7] Asakura, T., Kumiko, Y.K., Furitsu, H., Yusuke, S., Katsuyuki, N. and Kaji, N.H. (2014) Difference in the Structures of Alanine Tri- and Tetra-Peptides with Antiparallel β-Sheet Assessed by X-Ray Diffraction, Solid-State NMR and Chemical Shift Calculations by GIPAW. Biopolymers, 101, 13-20.
http://dx.doi.org/10.1002/bip.22241
[8] Palencár, P. and Bleha, T. (2011) Molecular Dynamics Simulations of the Folding of Poly (Alanine) Peptides. Journal of molecular Modeling, 17, 2367-2374.
http://dx.doi.org/10.1007/s00894-011-0997-4
[9] Mezei, M., Fleming P.J., Srinivasan, R. and Rose, G.D. (2004) Polyproline II Helix Is the Preferred Conformation for Unfolded Polyalanine in Water. Proteins: Structure Function and Bioinformatics, 55, 502-507.
http://dx.doi.org/10.1002/prot.20050
[10] Kentsis, A., Mezei, M., Gindin, T. and Osman, R. (2004) Unfolded State of Polyalanine Is a Segmented Polyproline II Helix. Proteins: Structure Function and Bioinformatics, 55, 493-501.
http://dx.doi.org/10.1002/prot.20051
[11] Soto, P., Baumketner, A. and Shea, J.E. (2006) Aggregation of Polyalanine in Hydrophobic Environment. Journal of Chemical Physics, 124, 134904-134907.
http://dx.doi.org/10.1063/1.2179803
[12] The PyMOL Molecular Graphics System, Version 1.5.0.4. Schrödinger, LLC, New York.
[13] Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A.E. and Berendsen, H.J.C. (2005) GROMACS: Fast, Flexible, and Free. Journal of Computational Chemistry, 26, 1701-1718.
http://dx.doi.org/10.1002/jcc.20291
[14] Van Gunsteren, W.F., et al. (1996) Biomolecular Simulation: The GROMOS 96 Manual and User Guide. VDF Hochschulverlag AG an der ETH Zürich, Zürich, 1-1042.
[15] Berendsen, H.J.C., Postma, J.P.M., van Gunsteren, W.F. and Hermans, J. (1981) Interaction Models for Water in Relation to Protein Hydration. In: Pullman, B., Ed., Intermolecular Forces, Springer, Berlin, 331-342.
[16] Bussi, G., Donadio, D. and Parrinello, M. (2007) Canonical Sampling through Velocity Rescaling. Journal of Chemical Physics, 126, Article ID: 014101.
http://dx.doi.org/10.1063/1.2408420
[17] Cuendet, M.A. and van Gunsteren, W.F. (2007) On the Calculation of Velocity-Dependent Properties in Molecular Dynamics Simulations Using the Leapfrog Integration Algorithm. Journal of Chemical Physics, 127, Article ID: 184102.
http://dx.doi.org/10.1063/1.2779878
[18] Hess, B., Bekker, H., Berendsen, H.J.C. and Fraaije, J.G.E.M. (1997) LINCS: A Linear Constraint Solver for Molecular Simulations. Journal of Computational Chemistry, 18, 1463-1472.
http://dx.doi.org/10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H
[19] Essmann, U., Perera, L., Berkowitz, M.L., Darden, T., Lee, H. and Pedersen, L.G. (1995) A Smooth Particle Mesh Ewald Method. Journal of Chemical Physics, 103, 8577-8592.
http://dx.doi.org/10.1063/1.470117
[20] Marqusee, S., Robbins, V.H. and Baldwin, R.L. (1989) Unusually Stable Helix Formation in Short Alanine-Based Peptides. Proceedings of the National Academy of Sciences of the United States of America, 86, 5286-5290.
http://dx.doi.org/10.1073/pnas.86.14.5286
[21] Nguyen, H.D. and Hall, C.K. (2004) Molecular Dynamics Simulations of Spontaneous Fibril Formation by Random-Coil Peptides. Proceedings of the National Academy of Sciences of the United States of America, 101, 16180-16185.
http://dx.doi.org/10.1073/pnas.0407273101
[22] Nguyen, H.D., Marchut, A.J. and Hall, C.K. (2004) Solvent Effects on the Conformational Transition of a Model Polyalanine Peptide. Protein Science, 13, 2909-2924.
http://dx.doi.org/10.1110/ps.04701304
[23] Graf, J., Nguyen, P.H., Stock, G. and Schwalbe, H. (2007) Structure and Dynamics of the Homologous Series of Alanine Peptides: A Joint Molecular Dynamics/NMR Study. Journal of the American Chemical Society, 129, 1179-1189.
http://dx.doi.org/10.1021/ja0660406
[24] Yamauchi, K., Okonogi, M., Kurosu, H., Tansho, M., Shimizu, T., Gullion, T. and Asakura, T. (2008) High Field 17O Solid-State NMR Study of Alanine Tripeptides. Journal of Magnetic Resonance, 190, 327-332.
http://dx.doi.org/10.1016/j.jmr.2007.11.006
[25] Scott, K.A., Alonso, D.O.V., Sato, S., Fersht, A.R. and Daggett, V. (2007) Conformational Entropy of Alanine versus Glycine in Protein Denatured States. Proceedings of the National Academy of Sciences of the United States of America, 104, 2661-2666.
http://dx.doi.org/10.1073/pnas.0611182104
[26] Mezei, M., Fleming, P.J., Srinivasan, R. and Rose, G.D. (2004) Polyproline II Helix Is the Preferred Conformation for Unfolded Polyalanine in Water. Proteins: Structure, Function, and Bioinformatics, 55, 502-507.
http://dx.doi.org/10.1002/prot.20050
[27] Bednárová, L., Maloň, P. and Bour, P. (2007) Spectroscopic Properties of the Nonplanar Amide Group: A Computational Study. Chirality, 19, 775-786.
http://dx.doi.org/10.1002/chir.20462
[28] Improta, R., Vitagliano, L. and Esposito, L. (2011) Peptide Bond Distortions from Planarity: New Insights from Quantum Mechanical Calculations and Peptide/Protein Crystal Structures. PLoS ONE, 6, e24533.
http://dx.doi.org/10.1371/journal.pone.0024533
[29] Platts, J.A., Maarof, H., Harris, K.D.M., Lim, G.K. and Willock, D.J. (2012) The Effect of Intermolecular Hydrogen Bonding on the Planarity of Amides. Physical Chemistry Chemical Physics, 14, 11944-11952.
http://dx.doi.org/10.1039/c2cp41716b
[30] López-Llano, J., Campos, L.A. and Sancho, J. (2006) α-Helix Stabilization by Alanine Relative to Glycine: Roles of Polar and Apolar Solvent Exposures and of Backbone Entropy. Proteins: Structure, Function, and Bioinformatics, 64, 769-778.
http://dx.doi.org/10.1002/prot.21041
[31] Chakarbourty, A., Schellman, J.A. and Baldwin, R.L. (1991) Large Differences in the Helix Propensities of Alanine and Glycine. Nature, 351, 586-588.
http://dx.doi.org/10.1038/351586a0
[32] Levitt, M. (1978) Conformational Preferences of Amino Acids in Globular Proteins? Biochemistry, 17, 4277-4285.
http://dx.doi.org/10.1021/bi00613a026
[33] Rohl, C.A., Chakrabartty, A. and Baldwin, R.L. (1996) Helix Propagation and N-Cap Propensities of the Amino Acids Measured in Alanine-Based Peptides in 40 Volume Percent Trifluoroethanol. Protein Science, 5, 2623-2637.
http://dx.doi.org/10.1002/pro.5560051225
[34] Rohrberg, J., Sachs, R., Lodderstedt, G., Sackewitz, M., Balbach, J. and Schwarz, E. (2008) Monitoring Fibril Formation of the N-Terminal Domain of PABPN1 Carrying an Alanine Repeat by Tryptophan Fluorescence and Real-Time NMR. FEBS Letters, 582, 1587-1592.
http://dx.doi.org/10.1016/j.febslet.2008.04.002
[35] Winter, R., Kühn, U., Hause, G. and Schwarz, E. (2012) Polyalanine-Independent Conformational Conversion of Nuclear Poly(A)-Binding Protein 1 (PABPN1). Journal of Biological Chemistry, 287, 22662-22671.
http://dx.doi.org/10.1074/jbc.M112.362327

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.