Abstract
The aggregation of proteins in the brain is one of the main features of neurodegenerative diseases. In Alzheimer’s disease, the abnormal aggregation of Aβ-42 is due to intrinsic and extrinsic factors. The latter is due to variations in the environment, such as temperature, salt concentration, and pH. We evaluated the effect of protonation/deprotonation of residues that are part of trimeric and pentameric oligomers at pH 5, pH 6, and pH 7. Molecular dynamics simulation at 200 ns in the canonical ensemble was implemented. The results have revealed that histidine, glutamic acid, and aspartic acid residues showed a protonation/deprotonation effect in oligomers. The root mean square deviation analysis was used to analyze the structural stability at different pHs. We found an increase in hydrophobicity in the side chains of the trimer, while in the pentamer, the structural instability of a compact structure at pH 5 caused the hydrophobic core to open, revealing the hydrophobic region to the environment. At this point, we believe that conformational changes mediated by pH are essential in the aggregation of Aβ-42 oligomers.
Similar content being viewed by others
References
Breydo L, Uversky VN (2015) Structural, morphological, and functional diversity of amyloid oligomers. FEBS Lett 589:2640–2648
Lim KH, Collver HH, Le YT, Nagchowdhuri P, Kenney JM (2007) Characterizations of distinct amyloidogenic conformations of the Aβ (1–40) and (1–42) peptides. Biochem Biophys Res Commun 353:443–449
Nasica-Labouze J, et al. (2015) Amyloid β protein and Alzheimer’s disease: when computer simulations complement experimental studies. Chem Rev 115:3518–3563
Hou L, Shao H, Zhang Y, Li H, Menon NK, Neuhaus EB, Brewer JM, Byeon I-JL, Ray DG, Vitek MP, Iwashita T, Makula RA, Przybyla AB, Zagorski MG (2004) Solution NMR studies of the Aβ(1–40) and Aβ(1–42) Peptides establish that the Met35 oxidation state affects the mechanism of amyloid formation. J Am Chem Soc 126:1992–2005
Grasso G, Rebella M, Muscat S, Morbiducci U, Tuszynski J, Danani A, Deriu MA (2018) Conformational dynamics and stability of U-shaped and S-shaped amyloid β assemblies. Int J Mol Sci 19:571
Petkova AT, Ishii Y, Balbach JJ, Antzutkin ON, Leapman RD, Delaglio F, Tycko R (2002) A structural model for Alzheimer’s β-amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci 99:16742–16747
Roychaudhuri R, Yang M, Hoshi MM, Teplow DB (2009) Amyloid β-protein assembly and Alzheimer disease. J Biol Chem 284:4749–4753
Tay WM, Huang D, Rosenberry TL, Paravastu AK (2013) The Alzheimer’s amyloid-β (1–42) peptide forms off-pathway oligomers and fibrils that are distinguished structurally by intermolecular organization. J Mol Biol 425:2494–2508
Larson ME, Lesné SE (2012) Soluble Aβ oligomer production and toxicity. J Neurochem 120:125–139
Wolff M, Zhang-Haagen B, Decker C, Barz B, Schneider M, Biehl R, Radulescu A, Strodel B, Willbold D, Nagel-Steger L (2493) Aβ42 pentamers/hexamers are the smallest detectable oligomers in solution. Sci Rep 2017:7
Tycko R (2014) Physical and structural basis for polymorphism in amyloid fibrils. Protein Science 23:1528–1539
Tycko R, Wickner RB (2013) Molecular structures of amyloid and prion fibrils: consensus versus controversy. Acc Chem Res 46:1487–1496
Miller Y, Ma B, Nussinov R (2010) Polymorphism in Alzheimer Aβ amyloid organization reflects conformational selection in a rugged energy landscape. Chem Rev 110:4820–4838
Zhao W, Ai H (2018) Effect of pH on Aβ42 monomer and fibril-like oligomers—decoding in silico of the roles of pK values of charged residues. Chem Phys Chem 19:1103–1116
Whittingham JL, Scott DJ, Chance K, Wilson A, Finch J, Brange J, Dodson GG (2002) Insulin at pH 2: structural analysis of the conditions promoting insulin fibre formation. J Mol Biol 318:479–490
Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416:507
Chiti F, Bucciantini M, Capanni C, Taddei N, Dobson CM, Stefani M (2001) Solution conditions can promote formation of either amyloid protofilaments or mature fibrils from the HypF N-terminal domain. Protein Science 10:2541–2547
Klug GM, Losic D, Supundi, Subasinghe S, Aguilar M-I, Martin LL, Small DH (2003) β-Amyloid protein oligomers induced by metal ions and acid pH are distinct from those generated by slow spontaneous ageing at neutral pH. Eur J Biochem 270:4282– 4293
Campioni S, Mannini B, Zampagni M, Pensalfini A, Parrini C, Evangelisti E, Relini A, Stefani M, Dobson CM, Cecchi C, Chiti F (2010) A causative link between the structure of aberrant protein oligomers and their toxicity. Nat Chem Biol 6:140
Bitan G, Vollers SS, Teplow DB (2003) Elucidation of primary structure elements controlling early amyloid β-protein oligomerization. J Biol Chem 278:34882–34889
Bernstein FC, Koetzle TF, Williams GJ, Meyer EF, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M (1977) The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol 112:535–542
Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E (2015) GROMACS High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1:19–25
Abraham M, van der Spoel D, Lindahl E, Hess B (2016) The GROMACS development team, GROMACS user m version 5.1 2, 2016. Gromac’s: the address of the publisher
Sambasivarao SV, Acevedo O (2009) Development of OPLS-AA force field parameters for 68 unique ionic liquids. J Chem Theory Comput 5:1038–1050
Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118:11225–11236
Makov G, Payne M (1995) Periodic boundary conditions in ab initio calculations. Phys Rev B 51:4014
Alper HE, Levy RM (1989) Computer simulations of the dielectric properties of water: studies of the simple point charge and transferrable intermolecular potential models. J Chem Phys 91:1242–1251
Evans DJ, Holian BL (1985) The Nose–Hoover thermostat. J Chem Phys 83:4069–4074
Humphrey W, Dalke A, Schulten K (1996) VMD: Visual molecular dynamics. Journal of Molecular Graphics 14:33–38
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612
Freddolino PL, Liu F, Gruebele M, Schulten K (2008) Ten-microsecond molecular dynamics simulation of a fast-folding WW domain. Biophys J 94:L75–L77
Ensign DL, Kasson PM, Pande VS (2007) Heterogeneity even at the speed limit of folding: large-scale molecular dynamics study of a fast-folding variant of the villin headpiece. J Mol Biol 374:806–816
Maragakis P, Lindorff-Larsen K, Eastwood MP, Dror RO, Klepeis JL, Arkin IT, Jensen MØ, Xu H, Trbovic N, Friesner RA et al (2008) Microsecond molecular dynamics simulation shows effect of slow loop dynamics on backbone amide order parameters of proteins. J Phys Chem B 112:6155–6158
Pérez A., Luque FJ, Orozco M (2007) Dynamics of b-DNA on the microsecond time scale. J Am Chem Soc 129:14739–14745
Klepeis JL, Lindorff-Larsen K, Dror RO, Shaw DE (2009) Long-timescale molecular dynamics simulations of protein structure and function. Curr Opin Struc Biol 19:120–127
Henzler-Wildman KA, Lei M, Thai V, Kerns SJ, Karplus M, Kern D (2007) A hierarchy of timescales in protein dynamics is linked to enzyme catalysis. Nature 450:913
Austin RH, Beeson K, Eisenstein L, Frauenfelder H, Gunsalus I (1975) Dynamics of ligand binding to myoglobin. Biochemistry 14:5355–5373
Vitkup D, Ringe D, Petsko GA, Karplus M (2000) Solvent mobility and the protein’glass’ transition. Nat Struct Mol Biol 7:34
Fenimore PW, Frauenfelder H, McMahon BH, Parak FG (2002) Slaving: solvent fluctuations dominate protein dynamics and functions. Proc Natl Acad Sci 99:16047–16051
Williams AD, Portelius E, Kheterpal I, Guo J-T, Cook KD, Xu Y, Wetzel R (2004) Mapping Aβ amyloid fibril secondary structure using scanning proline mutagenesis. J Mol Biol 335:833– 842
Touw WG, Baakman C, Black J, te Beek TA, Krieger E, Joosten RP, Vriend G (2014) A series of PDB-related databanks for everyday needs. Nucleic Acids Res 43:D364–D368
Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci 98:10037–10041
Forsyth WR, Antosiewicz JM, Robertson AD (2002) Empirical relationships between protein structure and carboxyl pKa values in proteins. Protein: Structure, Function, and Bioinformatics 48:388–403
Sancho J, Serrano L, Fersht AR (1992) Histidine residues at the N-and C-termini of α-helixes: perturbed pKas and protein stability. Biochemistry 31:2253–2258
Vaiana S, Manno M, Emanuele A, Palma-Vittorelli M, Palma M (2001) The role of solvent in protein folding and in aggregation. J Biol Phys 27:133–145
Funding
This study was financially supported by CONCYTEC under Project 139-2015 FONDECYT
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This paper belongs to Topical Collection QUITEL 2018 (44th Congress of Theoretical Chemists of Latin Expression)
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Paredes-Rosan, C.A., Valencia, D.E., Barazorda-Ccahuana, H.L. et al. Amyloid beta oligomers: how pH influences over trimer and pentamer structures?. J Mol Model 26, 1 (2020). https://doi.org/10.1007/s00894-019-4247-5
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00894-019-4247-5