Startseite The influence of glycine on β-lactoglobulin amyloid fibril formation – computer simulation study
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

The influence of glycine on β-lactoglobulin amyloid fibril formation – computer simulation study

  • Matej Jaklin ORCID logo , Sandi Brudar ORCID logo und Barbara Hribar-Lee ORCID logo EMAIL logo
Veröffentlicht/Copyright: 11. November 2024
Zeitschrift für Physikalische Chemie
Aus der Zeitschrift Zeitschrift für Physikalische Chemie Band 239 Heft 9

Abstract

Amyloids are protein aggregates involved in various protein condensation diseases. Our study aims to investigate the influence of glycine on the fibrillization mechanism of β-lactoglobulin (BLG), a model protein known to form amyloid fibrils from hydrolysed peptides in low pH aqueous solutions. We conducted atomistic molecular dynamics simulations of aqueous solutions of native and unfolded BLG in glycine buffer at pH 2.0. During the simulations we put our focus on analysing protein-protein/buffer interactions, structural electrostatic potential mapping, and the residence times of glycine and glycinium near specific amino acid residues. Glycinium cations were found to preferentially interact with specific protein residues potentially masking the outer disulfide bonds, affecting thiol deprotonation and influencing disulfide scrambling equilibrium. These interactions can potentially hinder hydrolysis and change the fibrillization pathway. Further investigations, such as constant pH MD simulations, simulations on disulfide bounded oligomers are warranted to validate these findings and deepen our understanding of protein aggregation mechanisms.

Keywords: fibrillization; beta-lactoglobulin; amyloids; MD
Corresponding author: Barbara Hribar-Lee, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot, 113, SI-1000 Ljubljana, Slovenia, E-mail:

Acknowledgments

The authors acknowledge the support from the National Institutes of Health (NIH) RM1 award “Solvation modeling for next-gen biomolecule simulations” (grant No. RM1GM135136).

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: National Institutes of Health (NIH) RM1, grant No. RM1GM135136.

  7. Data availability: The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

1. Zhang, Y.; Chen, H.; Li, R.; Sterling, K.; Song, W. Amyloid β-Based Therapy for Alzheimer’s Disease: Challenges, Successes and Future. Signal Transduct. Targeted Ther. 2023, 8 (1), 248. https://doi.org/10.1038/s41392-023-01484-7.Suche in Google Scholar PubMed PubMed Central

2. Jaunmuktane, Z.; Mead, S.; Ellis, M.; Wadsworth, J. D. F.; Nicoll, A. J.; Kenny, J.; Launchbury, F.; Linehan, J.; Richard-Loendt, A.; Walker, A. S.; Rudge, P.; Collinge, J.; Brandner, S. Evidence for Human Transmission of Amyloid-β Pathology and Cerebral Amyloid Angiopathy. Nature 2015, 525 (7568), 247–250. https://doi.org/10.1038/nature15369.Suche in Google Scholar PubMed

3. Tang, Y.; Zhang, D.; Zhang, Y.; Liu, Y.; Gong, X.; Chang, Y.; Ren, B.; Zheng, J. Introduction and Fundamentals of Human Islet Amyloid Polypeptide Inhibitors. ACS Appl. Bio Mater. 2020, 3 (12), 8286–8308. https://doi.org/10.1021/acsabm.0c01234.Suche in Google Scholar PubMed

4. Li, Y.; Yan, J.; Zhang, X.; Huang, K. Disulfide Bonds in Amyloidogenesis Diseases Related Proteins. Proteins Struct. Funct. Bioinf. 2013, 81 (11), 1862–1873. https://doi.org/10.1002/prot.24338.Suche in Google Scholar PubMed

5. Al Hamed, R.; Bazarbachi, A. H.; Bazarbachi, A.; Malard, F.; Harousseau, J.-L.; Mohty, M. Comprehensive Review of Al Amyloidosis: Some Practical Recommendations. Blood Cancer J. 2021, 11 (5), 97. https://doi.org/10.1038/s41408-021-00486-4.Suche in Google Scholar PubMed PubMed Central

6. Sawaya, M. R.; Sambashivan, S.; Nelson, R.; Ivanova, M. I.; Sievers, S. A.; Apostol, M. I.; Thompson, M. J.; Balbirnie, M.; Wiltzius, J. J. W.; McFarlane, H. T.; Madsen, A. Ø.; Riekel, C.; Eisenberg, D. Atomic Structures of Amyloid Cross-β Spines Reveal Varied Steric Zippers. Nature 2007, 447 (7143), 453–457. https://doi.org/10.1038/nature05695.Suche in Google Scholar PubMed

7. Fitzpatrick, A. W. P.; Debelouchina, G. T.; Bayro, M. J.; Clare, D. K.; Caporini, M. A.; Bajaj, V. S.; Jaroniec, C. P.; Wang, L.; Ladizhansky, V.; Müller, S. A.; MacPhee, C. E.; Waudby, C. A.; Mott, H. R.; De Simone, A.; Knowles, T. P. J.; Saibil, H. R.; Vendruscolo, M.; Orlova, E. V.; Griffin, R. G.; Dobson, C. M. Atomic Structure and Hierarchical Assembly of a Cross- Amyloid Fibril. Proc. Natl. Acad. Sci. 2013, 110 (14), 5468–5473. https://doi.org/10.1073/pnas.1219476110.Suche in Google Scholar PubMed PubMed Central

8. Schleeger, M.; vandenAkker, C. C.; Deckert-Gaudig, T.; Deckert, V.; Velikov, K. P.; Koenderink, G.; Bonn, M. Amyloids: From Molecular Structure to Mechanical Properties. Polymer 2013, 54 (10), 2473–2488. https://doi.org/10.1016/j.polymer.2013.02.029.Suche in Google Scholar

9. Otzen, D.; Riek, R. Functional Amyloids. Cold Spring Harbor Perspect. Biol. 2019, 11 (12). https://doi.org/10.1101/cshperspect.a033860.Suche in Google Scholar PubMed PubMed Central

10. Li, J.; Zhang, F. Amyloids as Building Blocks for Macroscopic Functional Materials: Designs, Applications and Challenges. Int. J. Mol. Sci. 2021, 22 (19). https://doi.org/10.3390/ijms221910698.Suche in Google Scholar PubMed PubMed Central

11. Sinnige, T. Molecular Mechanisms of Amyloid Formation in Living Systems. Chem. Sci. 2022, 13, 7080–7097. https://doi.org/10.1039/d2sc01278b.Suche in Google Scholar PubMed PubMed Central

12. Loveday, S. M.; Anema, S. G.; Singh, H. β-Lactoglobulin Nanofibrils: The Long and the Short of it. Int. Dairy J. 2017, 67, 35–45. https://doi.org/10.1016/j.idairyj.2016.09.011.Suche in Google Scholar

13. Cao, Y.; Mezzenga, R. Food Protein Amyloid Fibrils: Origin, Structure, Formation, Characterization, Applications and Health Implications. Adv. Colloid Interface Sci. 2019, 269, 334–356. https://doi.org/10.1016/j.cis.2019.05.002.Suche in Google Scholar PubMed

14. Adamcik, J.; Mezzenga, R. Proteins Fibrils from a Polymer Physics Perspective. Macromolecules 2012, 45 (3), 1137–1150. https://doi.org/10.1021/ma202157h.Suche in Google Scholar

15. Hoppenreijs, L. J. G.; Fitzner, L.; Ruhmlieb, T.; Heyn, T. R.; Schild, K.; van der Goot, A.-J.; Boom, R. M.; Steffen-Heins, A.; Schwarz, K.; Keppler, J. K. Engineering Amyloid and Amyloid-Like Morphologies of β-Lactoglobulin. Food Hydrocolloids 2022, 124, 107301. https://doi.org/10.1016/j.foodhyd.2021.107301.Suche in Google Scholar

16. Ke, P. C.; Zhou, R.; Serpell, L. C.; Riek, R.; Knowles, T. P. J.; Lashuel, H. A.; Gazit, E.; Hamley, I. W.; Davis, T. P.; Fändrich, M.; Otzen, D. E.; Chapman, M. R.; Dobson, C. M.; Eisenberg, D. S.; Mezzenga, R. Half a Century of Amyloids: Past, Present and Future. Chem. Soc. Rev. 2020, 49, 5473–5509. https://doi.org/10.1039/c9cs00199a.Suche in Google Scholar PubMed PubMed Central

17. Close, W.; Neumann, M.; Schmidt, A.; Hora, M.; Annamalai, K.; Schmidt, M.; Reif, B.; Schmidt, V.; Grigorieff, N.; Fändrich, M. Physical Basis of Amyloid Fibril Polymorphism. Nat. Commun. 2018, 9 (1), 699. https://doi.org/10.1038/s41467-018-03164-5.Suche in Google Scholar PubMed PubMed Central

18. Barbiroli, A.; Iametti, S.; Bonomi, F. Beta-Lactoglobulin as a Model Food Protein: How to Promote, Prevent, and Exploit its Unfolding Processes. Molecules 2022, 27 (3). https://doi.org/10.3390/molecules27031131.Suche in Google Scholar PubMed PubMed Central

19. Akkermans, C.; Venema, P.; Jan van der Goot, A.; Gruppen, H.; Bakx, E. J.; Boom, R. M.; van der Linden, E. Peptides Are Building Blocks of Heat-Induced Fibrillar Protein Aggregates of β-Lactoglobulin Formed at ph 2. Biomacromolecules 2008, 9 (5), 1474–1479. https://doi.org/10.1021/bm7014224.Suche in Google Scholar PubMed

20. Oboroceanu, D.; Wang, L.; Brodkorb, A.; Magner, E.; Auty, M. A. E. Characterization of Beta-Lactoglobulin Fibrillar Assembly Using Atomic Force Microscopy, Polyacrylamide Gel Electrophoresis, and In Situ Fourier Transform Infrared Spectroscopy. J. Agric. Food Chem. 2010, 58 (6), 3667–3673. https://doi.org/10.1021/jf9042908.Suche in Google Scholar PubMed

21. Loveday, S. M.; Wang, X. L.; Rao, M. A.; Anema, S. G.; Singh, H. -lactoglobulin Nanofibrils: Effect of Temperature on Fibril Formation Kinetics, Fibril Morphology and the Rheological Properties of Fibril Dispersions. Food Hydrocolloids 2012, 27 (1), 242–249. https://doi.org/10.1016/j.foodhyd.2011.07.001.Suche in Google Scholar

22. Dave, A. C.; Loveday, S. M.; Anema, S. G.; Loo, T. S.; Norris, G. E.; Jameson, G. B.; Singh, H. β-Lactoglobulin Self-Assembly: Structural Changes in Early Stages and Disulfide Bonding in Fibrils. J. Agric. Food Chem. 2013, 61 (32), 7817–7828. https://doi.org/10.1021/jf401084f.Suche in Google Scholar PubMed

23. Dave, A. C.; Loveday, S. M.; Anema, S. G.; Jameson, G. B.; Singh, H. Modulating β-Lactoglobulin Nanofibril Self-Assembly at ph 2 Using Glycerol and Sorbitol. Biomacromolecules 2013, 15 (1), 95–103. https://doi.org/10.1021/bm401315s.Suche in Google Scholar PubMed

24. Heyn, T. R.; Mayer, J.; Neumann, H. R.; Selhuber-Unkel, C.; Kwade, A.; Schwarz, K.; Keppler, J. K. The Threshold of Amyloid Aggregation of Beta-Lactoglobulin: Relevant Factor Combinations. J. Food Eng. 2020, 283, 110005. https://doi.org/10.1016/j.jfoodeng.2020.110005.Suche in Google Scholar

25. Adamcik, J.; Mezzenga, R. Adjustable Twisting Periodic Pitch of Amyloid Fibrils. Soft Matter 2011, 7, 5437–5443. https://doi.org/10.1039/c1sm05382e.Suche in Google Scholar

26. Lara, C.; Adamcik, J.; Jordens, S.; Mezzenga, R. General Self-Assembly Mechanism Converting Hydrolyzed Globular Proteins into Giant Multistranded Amyloid Ribbons. Biomacromolecules 2011, 12 (5), 1868–1875. https://doi.org/10.1021/bm200216u.Suche in Google Scholar PubMed

27. Reynolds, N. P.; Adamcik, J.; Berryman, J. T.; Handschin, S.; Zanjani, A. A. H.; Li, W.; Liu, K.; Zhang, A.; Mezzenga, R. Competition Between Crystal and Fibril Formation in Molecular Mutations of Amyloidogenic Peptides. Nat. Commun. 2017, 8 (1), 1338. https://doi.org/10.1038/s41467-017-01424-4.Suche in Google Scholar PubMed PubMed Central

28. VandenAkker, C. C.; Schleeger, M.; Bruinen, A. L.; Deckert-Gaudig, T.; Velikov, K. P.; Heeren, R. M. A.; Deckert, V.; Bonn, M.; Koenderink, G. H. Multimodal Spectroscopic Study of Amyloid Fibril Polymorphism. J. Phys. Chem. B 2016, 120 (34), 8809–8817. https://doi.org/10.1021/acs.jpcb.6b05339.Suche in Google Scholar PubMed

29. Loveday, S. M.; Wang, X. L.; Rao, M. A.; Anema, S. G.; Creamer, L. K.; Singh, H. Tuning the Properties of β-Lactoglobulin Nanofibrils with Ph, Nacl and Cacl2. Int. Dairy J. 2010, 20 (9), 571–579. https://doi.org/10.1016/j.idairyj.2010.02.014.Suche in Google Scholar

30. Zappone, B.; De Santo, M. P.; Labate, C.; Rizzuti, B.; Guzzi, R. Catalytic Activity of Copper Ions in the Amyloid Fibrillation of β-Lactoglobulin. Soft Matter 2013, 9, 2412–2419. https://doi.org/10.1039/c2sm27408f.Suche in Google Scholar

31. Guzzi, R.; Rizzuti, B.; Labate, C.; Zappone, B.; De Santo, M. P. Ferric Ions Inhibit the Amyloid Fibrillation of β-Lactoglobulin at High Temperature. Biomacromolecules 2015, 16 (6), 1794–1801. https://doi.org/10.1021/acs.biomac.5b00371.Suche in Google Scholar PubMed

32. Loveday, S. M.; Wang, X. L.; Rao, M. A.; Anema, S. G.; Singh, H. Effect of Ph, Nacl, Cacl2 and Temperature on Self-Assembly of β-Lactoglobulin into Nanofibrils: A Central Composite Design Study. J. Agric. Food Chem. 2011, 59 (15), 8467–8474. https://doi.org/10.1021/jf201870z.Suche in Google Scholar PubMed

33. Gosal, W. S.; Clark, A. H.; Ross-Murphy, S. B. Fibrillar β-Lactoglobulin Gels: Part 1. Fibril Formation and Structure. Biomacromolecules 2004, 5 (6), 2408–2419. https://doi.org/10.1021/bm049659d.Suche in Google Scholar PubMed

34. Hamada, D.; Dobson, C. M. A Kinetic Study of Beta-Lactoglobulin Amyloid Fibril Formation Promoted by Urea. Protein Sci. 2002, 11 (10), 2417–2426. https://doi.org/10.1110/ps.0217702.Suche in Google Scholar PubMed PubMed Central

35. Rasmussen, P.; Barbiroli, A.; Bonomi, F.; Faoro, F.; Ferranti, P.; Iriti, M.; Picariello, G.; Iametti, S. Formation of Structured Polymers upon Controlled Denaturation of β-Lactoglobulin with Different Chaotropes. Biopolymers 2007, 86 (1), 57–72. https://doi.org/10.1002/bip.20704.Suche in Google Scholar PubMed

36. Brudar, S.; Hribar-Lee, B. Effect of Buffer on Protein Stability in Aqueous Solutions: A Simple Protein Aggregation Model. J. Phys. Chem. B 2021, 125 (10), 2504–2512. https://doi.org/10.1021/acs.jpcb.0c10339.Suche in Google Scholar PubMed PubMed Central

37. Ugwu, S. O.; Apte, S. The Effect of Buffers on Protein Conformational Stability. Pharm. Technol. 2004, 28, 86–108.Suche in Google Scholar

38. Brudar, S.; Hribar-Lee, B. The Role of Buffers in Wild-Type HEWL Amyloid Fibril Formation Mechanism. Biomolecules 2019, 9 (2). https://doi.org/10.3390/biom9020065.Suche in Google Scholar PubMed PubMed Central

39. Jaklin, M.; Hritz, J.; Hribar-Lee, B. A New Fibrillization Mechanism of β-Lactoglobulin in glycine Solutions. Int. J. Biol. Macromol. 2022, 216, 414–425. https://doi.org/10.1016/j.ijbiomac.2022.06.182.Suche in Google Scholar PubMed PubMed Central

40. Wu, S.-Y.; Pérez, M. D.; Puyol, P.; Sawyer, L. β-Lactoglobulin Binds Palmitate within its Central Cavity*. J. Biol. Chem. 1999, 274 (1), 170–174. https://doi.org/10.1074/jbc.274.1.170.Suche in Google Scholar PubMed

41. Jurrus, E.; Engel, D.; Star, K.; Monson, K.; Brandi, J.; Felberg, L. E.; Brookes, D. H.; Wilson, L.; Chen, J.; Liles, K.; Chun, M.; Li, P.; Gohara, D. W.; Dolinsky, T.; Konecny, R.; Koes, D. R.; Nielsen, J. E.; Head-Gordon, T.; Geng, W.; Krasny, R.; Wei, G.-W.; Holst, M. J.; McCammon, J. A.; Baker, N. A. Improvements to the APBS Biomolecular Solvation Software Suite. Protein Sci. 2018, 27 (1), 112–128. https://doi.org/10.1002/pro.3280.Suche in Google Scholar PubMed PubMed Central

42. Abraham, M. J.; Murtola, T.; Schulz, R.; Páll, S.; Smith, J. C.; Hess, B.; Lindahl, E. Gromacs: High Performance Molecular Simulations Through Multi-Level Parallelism from Laptops to Supercomputers. SoftwareX 2015, 1-2, 19–25. https://doi.org/10.1016/j.softx.2015.06.001.Suche in Google Scholar

43. Dodda, L. S.; Cabeza de Vaca, I.; Tirado-Rives, J.; Jorgensen, W. L. LigParGen Web Server: an Automatic OPLS-AA Parameter Generator for Organic Ligands. Nucleic Acids Res. 2017, 45 (W1), W331–W336. https://doi.org/10.1093/nar/gkx312.Suche in Google Scholar PubMed PubMed Central

44. Robertson, M. J.; Tirado-Rives, J.; Jorgensen, W. L. Improved Peptide and Protein Torsional Energetics with the Opls-Aa Force Field. J. Chem. Theory Comput. 2015, 11 (7), 3499–3509. https://doi.org/10.1021/acs.jctc.5b00356.Suche in Google Scholar PubMed PubMed Central

45. Berendsen, H. J. C.; Grigera, J. R.; Straatsma, T. P. The Missing Term in Effective Pair Potentials. J. Phys. Chem. 1987, 91 (24), 6269–6271. https://doi.org/10.1021/j100308a038.Suche in Google Scholar

46. Mochizuki, K.; Sumi, T.; Koga, K. Liquid–Liquid Phase Separation of N-Isopropylpropionamide Aqueous Solutions above the Lower Critical Solution Temperature. Sci. Rep. 2016, 6 (1), 24657. https://doi.org/10.1038/srep24657.Suche in Google Scholar PubMed PubMed Central

47. Mthembu, S. N.; Sharma, A.; Albericio, F.; de la Torre, B. G. Breaking a Couple: Disulfide Reducing Agents. Chembiochem 2020, 21 (14), 1947–1954. https://doi.org/10.1002/cbic.202000092.Suche in Google Scholar PubMed

48. Martins de Oliveira, V.; Liu, R.; Shen, J. Constant Ph Molecular Dynamics Simulations: Current Status and Recent Applications. Curr. Opin. Struct. Biol. 2022, 77, 102498. https://doi.org/10.1016/j.sbi.2022.102498.Suche in Google Scholar PubMed PubMed Central

49. da Rocha, L.; Baptista, A. M.; Campos, S. R. R. Approach to Study pH-Dependent Protein Association Using Constant-pH Molecular Dynamics: Application to the Dimerization of β-Lactoglobulin. J. Chem. Theory Comput. 2022, 18 (3), 1982–2001. https://doi.org/10.1021/acs.jctc.1c01187.Suche in Google Scholar PubMed PubMed Central

Received: 2024-02-28
Accepted: 2024-09-10
Published Online: 2024-11-11
Published in Print: 2025-09-25

© 2024 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Preface
  3. Preface
  4. Contribution to “From Nanostructure to Function”
  5. Temporal airy pulses efficiency in thin glass dicing
  6. Surface investigations of bronze and brass statuary monuments in open-air exposure
  7. Dual dynamic voltammetric study of the formation of ferrate ions during the electrochemical dissolution of white cast iron in the transpassive region
  8. Cetuximab-induced changes to tumor oral mucosa models probed by stimulated Raman spectromicroscopy
  9. From nanostructure to function: hierarchical functional structures in chitin and keratin
  10. The influence of glycine on β-lactoglobulin amyloid fibril formation – computer simulation study
https://doi.org/10.1515/zpch-2024-0761
Schlagwörter für diesen Artikel
fibrillization; beta-lactoglobulin; amyloids; MD

Artikel in diesem Heft

  1. Frontmatter
  2. Preface
  3. Preface
  4. Contribution to “From Nanostructure to Function”
  5. Temporal airy pulses efficiency in thin glass dicing
  6. Surface investigations of bronze and brass statuary monuments in open-air exposure
  7. Dual dynamic voltammetric study of the formation of ferrate ions during the electrochemical dissolution of white cast iron in the transpassive region
  8. Cetuximab-induced changes to tumor oral mucosa models probed by stimulated Raman spectromicroscopy
  9. From nanostructure to function: hierarchical functional structures in chitin and keratin
  10. The influence of glycine on β-lactoglobulin amyloid fibril formation – computer simulation study
Jetzt anmelden und 20% sparen
Institutioneller Zugang
Wie funktioniert Authentifizierung?
Haben Sie eine Idee, wie wir unsere Website verbessern können?
Bitte schreiben Sie uns.
© 2025 De Gruyter Brill
Heruntergeladen am 3.12.2025 von https://www.degruyterbrill.com/document/doi/10.1515/zpch-2024-0761/pdf?lang=de
Button zum nach oben scrollen