Kouza, M.

Lam, N. S.

Li, M. S.

Zung, H.

Juelich Shared Electronic Resources

John von Neumann Institute for ComputingInhibition of Fibril Formation ofBeta-Amyloid PeptidesN. S. Lam, M. Kouza, H. Zung, M. S. Lipublished inFrom Computational Biophysics to Systems Biology (CBSB08),Proceedings of the NIC Workshop 2008,Ulrich H. E. Hansmann, Jan H. Meinke, Sandipan Mohanty,Walter Nadler, Olav Zimmermann (Editors),John von Neumann Institute for Computing, Ju¨lich,NIC Series, Vol. 40, ISBN 978-3-9810843-6-8, pp. 121-124, 2008.c© 2008 by John von Neumann Institute for ComputingPermission to make digital or hard copies of portions of this work forpersonal or classroom use is granted provided that the copies are notmade or distributed for profit or commercial advantage and that copiesbear this notice and the full citation on the first page. To copy otherwiserequires prior specific permission by the publisher mentioned above.http://www.fz-juelich.de/nic-series/volume40Inhibition of Fibril Formation of Beta-Amyloid PeptidesNguyen Sy Lam1, Maksim Kouza2, Hoang Zung1, and Mai Suan Li21 Computational Physics Lab, Vietnam National University,Ho Chi Minh city, 227 Nguyen Van Cu, Dist. 5, Vietnam2 Institute of Physics, Polish Academy of Sciences,Al. Lotnikow 32/46, 02-668 Warsaw, PolandE-mail: masli@ifpan.edu.plAlzheimer’s, Parkinson’s, Huntington’s, type II diabetes, and Mad Cow disease, or Cystic fi-brosis, these apparently unrelated diseases, the so-called protein structural diseases, are foundto be a result of protein misfolding. Understanding the role of molecular inhibitors in formationof amyloid fibrils plays an important role in finding proper treatments to those structural dis-eases. In the case of Alzheimer’s disease, experiments showed that the fibrillation of full-lengthAβ peptides is disrupted by the peptide fragment Aβ16−20 (KLVFF). In this contribution,we studied the kinetics of oligomerization of the system of two Aβ16−22 and one Aβ16−20peptides, using all-atom simulations with the GROMOS96 force field 43a1 in explicit water.In agreement with experiments, Aβ16−20 peptide was found to slow down the aggregationprocess.1 IntroductionIn many cases protein aggregates take the form of amyloid fibrils, which appear as un-branched rod-like nanostructures with the diameter of an order of 10 nm and varyinglength1. A large body of evidence suggests that amyloid fibrils and associated oligomericintermediates are related to a number of diseases, including Alzheimer’s, Parkinson’s,Huntington’s, and prion diseases1. For example, in the case of the Alzheimer’s diseasethe memory decline may result from the accumulation of the amyloid β-proteins (Aβ)present in two forms - 40 (Aβ1−40) and 42 (Aβ1−42) amino acids of which are producedthrough endoproteolysis of the β-amyloid precursor transmembrane protein. Since struc-tural diseases affect a significant portion of senior population, it is vital to develop ther-apeutic approaches to combat the amyloid assembly. One of possible ways is to designmolecular inhibitors, which interfere with this process. For example, the peptide fragmentAβ16−20 KLVFF2 and the peptide LPFFD derived from Aβ17−21 fragment by V18P andA21D mutations3 can disrupt fibrillation of full-length Aβ peptide. An insertion of prolinesalso inhibits amyloid formation. An another powerful strategy for inhibition is a peptideN-methylation. It was demonstrated that themembrane-permeable NN-methylated pen-tapeptide Aβ16− 20m is an effective fibrillogenesis inhibitor, capable of both preventingfibril growth and disassembling existing fibrils4In this contribution, we study the influence of a pentapeptide Aβ16−20 on the kinet-ics of oligomerization of longer Aβ16−22 peptides, using all-atom simulations with theGROMOS96 force field 43a1 in explicit water5. Since the fibril formation time tfibrilof a system of two Aβ16−22 and one Aβ16−20 peptide is much longer than that for threeAβ16−22 peptides, one can expect that, in agreement with experiments2, Aβ16−20 fragmentslows down the fibril growth process.121Figure 1. The free energy landscape as a function of V1 and V2. Typical conformations of some local minimaare shown.2 Method and ResultsThe structures of monomeric Aβ16−20 and Aβ16−22 were extracted from the structure ofAβ10−35 peptide available in the Protein Data Bank (ID: 1hz3). In order to study con-formation changes of a monomer Aβ16−20, one trajectory of 150 ns was generated. Theinitial configuration of the system of two Aβ16−22 and one Aβ16−20 was created by ran-domly placing these peptides in a periodic box of volume 78 nm3 which corresponds tothe peptide concentration of 64 mM. For this system, four runs of 300, 343, 453, and 484ns were carried out. All simulations were performed at T = 300 K.We used the dihedral principal component analysis6 to compute the free energy land-scapes (FEL), using the first two eigenvectors V1 and V2. In order to monitor the fibrilformation process, we use the ”liquid crystal” order parameter P2. If P ≥ 0.9 then thesystem is considered to be in the fibril-like state6.Fig. 1 shows the free energy of a monomer Aβ16−20 as a function of V1 and V2. Theexistence of many shallow local minima separated by low barriers (of only a few kBT )122Figure 2. Time dependence of P2 for the (2Aβ16−22+Aβ16−20) system. Shown is the structure at the largestP2 ≈ 0.75. Interestingly, one Aβ16−22 and one Aβ16−20 adopt anti-parallel arrangement.suggests that the system is not stable under thermal fluctuations. As evident from typi-cal snapshots (Fig. 1), the monomer adopts mainly coil conformations. Comparing withthe free energy landscape of Aβ16−226, one can see that the pentapeptide Aβ16−20 is lessstable than Aβ16−22. This may be a reason why Aβ16−20 can serve as an inhibitor foroligomerization of Aβ16−22 peptides, because in some situations proteins which have amore ordered structure in the monomeric state, are expected to be more prone to aggrega-tion.The time dependence of the order parameter P2 for the (2Aβ16−22+Aβ16−20) systemis shown in Fig. 2. Since the largest value P2 ≈ 0.76, found at t ≈ 64 ns, is lower than0.9, a fibril-like state does not occur in this run. This state was also not observed for threeother trajectories (results not shown). Therefore, for the (2Aβ16−22+Aβ16−20) system,tfibril > 400 ns, which is larger than tfibril ≈ 200 ns for a system of three Aβ16−22peptides6. This result suggests that, in agreement with the experiment2, Aβ16−20 caninterfere with the oligomerization process. There are two possible reasons for this:(a) Aβ16−20 does not contain the negatively charged glutamic acid (E) as Aβ16−22 does.(b) The replacement of Aβ16−22 by KLVFF reduces hydrophobicity of the whole system.123In conclusion, we have shown that a short peptide KLVFF can inhibit the oligomer-ization of a system of Aβ16−22 peptides. It is expected to prevent the fibril growth offull-length Aβ peptides, due to charge imbalance.AcknowledgmentsThis work was supported by the Ministry of Science and Informatics in Poland (grant No202-204-234).References1. F. Chiti, and C. M. Dobson, Protein misfolding, functional amyloid, and human dis-ease, Annual Rev. Biochemistry 75, 333–366, 2006.2. L. O. Tjernberg et al., Arrest of β-amyloid fibril formation by a pentapeptide ligand,J. Biol. Chem. 271, 8545-8548, 1996.3. C. M. Soto, S. Kindy, M. Baumann, and B. Frangione, Inhibition of Alzheimer’samyloidosis by peptides that prevent β-sheet conformation,Biochem. Biophys. Res.Commun. 226, 672-680, 1996.4. D. J. Gordon, R. Tape, and S. C. Meredith, Design and characterization of a mem-brane permeable N-methyl amico acid-containing peptide that inhibit Aβ1−40 fibrilo-genesis, J. Pep. Res. 60, 37-55, 2003.5. H. J. C. Berendsen, D. van der Spoel and R. van Drunen, A message-passing parallelmolecular dynamics implementation, Comp. Phys. Comm. 91, 43–56, 1995.6. P. H. Nguyen, M. S. Li, G. Stock, J. E. Straub, and D. Thirumalai, Monomer adds topreformed structured oligomers of Aβ-peptides by a two-stage dock-lock mechanism,Proc. Natl. Acad. Sci. USA 104, 111–116, 2007.124

Inhibition of Fibril Formation of Beta-Amyloid Peptides

http://juser.fz-juelich.de/record/153010/files/FZJ-2014-02679.pdf

Inhibition of Fibril Formation of Beta-Amyloid Peptides

Abstract

Similar works

Full text

Available Versions

Juelich Shared Electronic Resources