The Role of E27-K31 and E56-K10 Salt-Bridge Pairs in the Unfolding Mechanism of the B1 Domain of Protein G

https://doi.org/10.22146/ijc.23934

Tony Ibnu Sumaryada(1*), Kania Nur Sawitri(2), Setyanto Tri Wahyudi(3)

(1) Department of Physics, Bogor Agricultural University
(2) Physics Education Program, Jambi University
(3) Department of Physics, Bogor Agricultural University
(*) Corresponding Author

Abstract


Molecular dynamics simulations of the B1 fragment of protein G (56 residues) have been performed at 325, 350, 375, 400, 450 and 500 K for 10 ns. An analysis of its structural and energetic parameters has indicated that the unfolding process of the GB1 protein begins at 900 ps of a 500-K simulation. The unfolding process is initiated when hydrogen bonds in the hydrophobic core region are broken; it continues with the α-helix transformation into coils and turns and ends with the destruction of the β-hairpins. These unfolding events are consistent with the hybrid model of the protein folding/unfolding mechanism, which is a compromise between the hydrophobic core collapse model and the zipper model. Salt-bridge pairs were found to play an important role in the unfolding process by maintaining the integrity of the tertiary structure of the protein. The breaking (or disappearance) of the salt-bridge pairs E27–K31 (in the α-helix) and E56–K10 (connecting β4 and β1) has resulted in the destruction of secondary structures and indicates the beginning of the unfolding process. Our results also suggest that the unfolding process in this simulation was not a complete denaturation of the protein because some β-hairpins remained

Keywords


protein G; molecular dynamics; protein folding; hybrid model; salt-bridge pairs

Full Text:

Full Text PDF


References

[1] Selkoe, D.J., 2004, Cell biology of protein misfolding: The examples of Alzheimer's and Parkinson's diseases, Nat. Cell Biol., 6 (11), 1054–1061.

[2] Dobson, C.M., 2003, Protein folding and misfolding, Nature, 426 (6968), 884–890.

[3] Chiti, F., and Dobson, C.M., 2006, Protein misfolding, functional amyloid, and human disease, Annu. Rev. Biochem., 75, 333–366.

[4] Pande, V.S., and Rokhsar, D.S., 1999, Molecular dynamics simulations of unfolding and refolding of a β-hairpin fragment of protein G, Proc. Natl. Acad. Sci. U.S.A., 96 (16), 9062–9067.

[5] Day, R, Bennion, B.J., Ham, S., and Daggett, V., 2002, Increasing temperature accelerates protein unfolding without changing the pathway of unfolding, J. Mol. Biol., 322 (1), 189–203.

[6] Gronenborn, A.M., Filpula, D.R., Essig, N.Z., Achari, A., Whitlow, M., Wingfield, P.T., and Clore, G.M., 1991, A novel, highly stable fold of the immunoglobulin binding domain of streptococcal protein G, Science, 253 (5020), 657–661.

[7] Morrone, A., Giri, R., Toofanny, R.D., Travaglini-Allocatelli, C., Brunori, M., Daggett, V., and Gianni, S., 2011, GB1 is not a two-state folder: Identification and characterization of an on-pathway intermediate, Biophys. J., 101 (8), 2053–2060.

[8] Kobayashi, N., Honda, S., Yoshii, H., Uedaira, H., and Munekata, E., 1995, Complement assembly of two fragments of the streptococcal protein G B1 domain in aqueous solution, FEBS Lett., 366 (2-3), 99–103.

[9] Sloan, D.J., and Hellinga, H.W.,1999, Dissection of the protein G B1 domain binding site for human IgG Fc fragment, Protein Sci., 8 (8), 1643–1648.

[10] Liu, J., Liao, C., and Zhou J., 2013, Multiscale simulations of protein G B1 adsorbed on charged self-assembled monolayers, Langmuir, 29 (36), 11366–11374.

[11] Roccatano, D., Amadei, A., Di Nola, A., and Berendsen, H.J., 1999, A molecular dynamics study of the 41–56 beta-hairpin from B1 domain of protein G, Protein Sci., 8 (10), 2130–2143.

[12] Lee, J., and Shin, S., 2001, Understanding beta-hairpin formation by molecular dynamics simulations of unfolding, Biophys. J., 81 (5), 2507–2516.

[13] Klimov, D.K., and Thirumalai, D., 2000, Mechanisms and kinetics of β-hairpin formation, Proc. Natl. Acad. Sci. U.S.A., 97 (6), 2544–2549.

[14] Zhou, R., Berne, B.J., and Germain, R., 2001, The free energy landscape for beta hairpin folding in explicit water, Proc. Natl. Acad. Sci. U.S.A., 98 (26), 14931–14936.

[15] Ma, B., and Nussinov, R., 2000, Molecular dynamics simulations of a beta-hairpin fragment of protein G: Balance between side-chain and backbone force, J. Mol. Biol., 296 (4), 1091–1104.

[16] Bui, J.M., Gsponer, J., Vendruscolo, M., and Dobson, C.M., 2009, Analysis of sub-τc and supra-τc motions in protein Gβ1 using molecular dynamics simulations, Biophys. J., 97 (9), 2513–2520.

[17] Kouza, M., and Hansmann, U.H.E., 2012, Folding simulations of the A and B domain of protein G, J. Phys. Chem. B, 116 (23), 6645–6653.

[18] Ceruso, M.A., Grottesi, A., and Di Nola, A., 1999, Mechanics and dynamics of B1 domain of protein G: Role of packing and surface hydrophobic residues, Protein Sci., 8 (1), 436–446.

[19] McCallister, E.L., Alm, E., and Baker, D., 2000, Critical role of β-hairpin formation in protein G folding, Nat. Struct. Biol., 7 (8), 669–673.

[20] Sheinerman, F.B., and Brooks, C.L., 1998, Calculations on folding of segment B1 of streptococcal protein G1, J. Mol. Biol., 278 (2), 439–456.

[21] Sheinerman, F.B., and Brooks, C.L., 1997, A molecular dynamics simulation study of segment β1 of protein G, Proteins, 29 (2), 193–202.

[22] Muñoz, V., Thompson, P.A., Hofrichter, J., and Eaton, W.A., 1997, Folding dynamics and Mechanism of β-hairpin formation, Nature, 390, 196–199.

[23] Zagrovic, B., Sorin, E.J., and Pande, V., 2001, Beta-hairpin folding simulations in atomistic detail using an implicit solvent model, J. Mol. Biol., 313 (1), 151–169.

[24] Clarke, S., 1981, The hydrophobic effect: Formation of micelles and biological membranes, J. Chem. Educ., 58 (8), 246.

[25] García, A.E., and Sanbonmatsu, K.Y., 2001, Exploring the energy landscape of a beta hairpin in explicit solvent, Proteins, 42 (3), 345–354.

[26] Tsai, J., and Levitt, M., 2002, Evidence of turn and salt bridge contributions to β-hairpin stability: MD simulations of C-terminal fragment from the B1 domain of protein G, Biophys. Chem., 101-102, 187–201.

[27] Humphrey, W., Dalke, A., and Schulten, K., 1996, VMD-Visual Molecular Dynamics, J. Mol. Graphics, 14 (1), 33–38.

[28] Phillips, J.C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., Chiot, C., Skeel, R.D., Kalé, L., and Schulten, K., 2005, Scalable molecular dynamics with NAMD, J. Comput. Chem., 26 (16), 1781–1802.

[29] Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Chandrasekhar, J., Impey, R.W., and Klein, M.L., 1983, Comparison of simple potential functions for simulating liquid water, J. Chem. Phys., 79 (2), 926–935.

[30] Guo, C., Levine, H., and Kessler, D.A., 2000, How does a beta-hairpin fold/unfold? Competition between topology and heterogeneity in a solvable model, Proc. Natl. Acad. Sci. U.S.A., 97 (20), 10775–10779.

[31] Kmiecik, S., and Kolinski, A., 2008, Folding pathway of the B1 domain of protein G explored by multiscale modeling, Biophys. J., 94 (3), 726–736.

[32] Bryant, Z., Pande, V.S., and Rokhsar, D.S., 2000, Mechanical unfolding of a β-hairpin using molecular dynamics, Biophys. J., 78 (2), 584–589.

[33] Blanco, F.J., Serrano, L., and Rivas, G., 1995, A short linear peptide that folds into a native stable β-hairpin in aqueous solution, Nat. Struct. Biol., 1 (9), 584–590.

[34] Alexander, P., Orban, J., and Bryan, P., 1992, Kinetic analysis of folding and unfolding the 56 amino acid IgG-binding domain of streptococcal protein G, Biochemistry, 31 (32), 7243–7248.

[35] Chung, H.S., Louis, J.M., and Eaton, W.A., 2010, Distinguishing between protein dynamics and dye photophysics in single-molecule FRET experiments, Biophys. J., 98 (4), 696–706.

[36] Shimada, J., and Shakhnovich, E.I., 2002, The ensemble folding kinetics of protein G from an all-atom Monte Carlo simulation, Proc. Natl. Acad. Sci. U.S.A., 99 (17), 11175–11180.



DOI: https://doi.org/10.22146/ijc.23934

Article Metrics

Abstract views : 948 | views : 1234


Copyright (c) 2017 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

 


Indonesian Journal of Chemisty (ISSN 1411-9420 / 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Web
Analytics View The Statistics of Indones. J. Chem.