Adler-Abramovich, L.

Archontis, G.

Gazit, E.

Tamamis, P.

Juelich Shared Electronic Resources

John von Neumann Institute for ComputingInsights into the Self-Assembly ofPhenylalanine Oligopeptides by ReplicaExchange MD Simulations with the GBSWImplicit-Solvent ModelP. Tamamis, L. Adler-Abramovich, E. Gazit, G. Archontispublished 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. 393-396, 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/volume40Insights into the Self-Assembly of PhenylalanineOligopeptides by Replica Exchange MD Simulations withthe GBSW Implicit-Solvent ModelPhanourios Tamamis1, Lihi Adler-Abramovich2,Ehud Gazit2, and Georgios Archontis11 Department of Physics, University of Cyprus, PO20537, CY1678 Nicosia, CyprusE-mail: tamamis@ucy.ac.cy2 Department of Molecular Microbiology and Biotechnology, Tel Aviv University,Tel Aviv 69978, IsraelThe diphenylalanine peptide (FF), the core recognition motif of the Alzheimer’s β-amyloidpeptide, self-assembles into tubular structures of high stability. We have studied the aggrega-tion properties of FF and the related triphenylalanine peptide (FFF) by 0.4-µs implicit- solventReplica Exchange MD simulations of aqueous FF and FFF solutions. The FF and FFF peptidesform ellipsoidal aggregates with a similar density and shape in the simulations. Within eachaggregate, we observe structural features, which are consistent with the properties of L-Phe-L-Phe crystals. In particular, the aromatic planes of interacting sidechains are mainly orientedperpendicular to each other and the backbone moieties of several (2-6) adjacent peptides in-teract frequently by head (NH3+) -to-tail (−OOC) hydrogen bonds, forming open or closed(ring-like) linear networks. The ring networks of six peptides observed in the FF simulationsare reminiscent of the hexagonal FF rings in the L-Phe-L-Phe crystals. The rings are energet-ically more stable than the open networks, due to both non-polar and polar interactions. Thenetwork propensity is higher in the FFF solution, mainly due to stronger non-polar and to asmaller extent due to stronger polar interactions in the networks of the FFF aggregate; in linewith this observation is the somewhat higher stability of the FFF aggregate, observed in thesimulations.1 IntroductionThe ability of short peptide fragments to self-assemble into amyloids1, nanotubes2 and sys-tems responsive to external stimuli (pH, temperature, concentration of specific solutes)3is the focus of intense experimental and computational studies in recent years, as it canprovide insights on the formation of amyloid fibers and has potential applications in bio-material synthesis, nanodevice fabrication and tissue engineering.The diphenylalanine peptide (NH2-L-Phe-L-Phe-COOH, FF), the core recognition mo-tif of the Alzheimer’s β-amyloid peptide was already been crystallized4. Under certainconditions the diphenylalanine peptide self assembles into nanotubes of remarkable stiff-ness5, which can serve as casts for the fabrication of silver nanowires6. In the crystals,the FF peptides are hydrogen-bonded head-to-tail, forming helical chains with six pep-tides per helical turn and a 10-A˚ van der Waals diameter4. Adjacent helices are orientedparallel to each other and interact extensively via an intricate three-dimensional stackingarrangement of the aromatic side chains. This structural information provides some hintsfor the molecular organization of the peptide nanotubes7. Nevertheless, the understandingof the key factors responsible for the nanotube stabilization is still not complete. For ex-ample, the peptide Ac-Phe-Phe-NH2 forms highly-ordered tubular structures despite the393lack of charge in its terminal ends, suggesting that the interactions between the aromaticsidechains rather than the electrostatic backbone interactions play the key role in the self-assembly process. At the same time, chemical modifications of the FF terminal ends causethe formation of macroscopic hydrogels8 or amyloid-like fibers9, suggesting that the nanos-tructures formed by FF depend also on the chemical nature and interactions of its terminalends.To obtain further insights on the aggregation properties of these systems, in the presentstudy we investigate by MD simulations the properties of aqueous solutions formed by FFand the related system, triphenylalanine peptide (NH2-FFF-COOH).2 Systems and MethodsAll simulations were performed with the CHARMM program, version c35a110. We simu-lated two aqueous solutions, consisting of 12 FF dipeptides and 8 FFF tripeptides, respec-tively. The peptides were placed in a 57-A˚ cubic box, modeling 34 mgr/ml (FF) and 33mgr/ml (FFF) solutions. The box was replicated by periodic boundary conditions. Thepeptide atomic charges, van der Waals and stereochemical parameters were taken from theCHARMM27 all-atom force field11, 12. The aqueous solvent effects were modeled implic-itly by the Generalized Born approximation GBSW13, 14. To improve the conformationalsampling, each solution was simulated by the replica-exchange scheme, with 10 replicasspanning the temperature ranges 289-405 K (FF) and 288-416 K (FFF). The replica tem-peratures were optimized iteratively in the beginning of the simulations as in ref. 15, 16,targeting a uniform exchange probability of 18-20% among adjacent replicas. The simu-lation length for each temperature was 40 ns, yielding a total simulation time of 0.4 µs forthe 10 replicas. Replica exchanges were attempted at 10-ps intervals. The analysis wasdone with the CHARMM modules and in-house FORTRAN programs.3 Results and DiscussionGeometrical Analysis: In both solutions the peptides form approximately ellipsoidal ag-gregates, which are stable at 300 K. The geometrical properties of the aggregates in the300-K simulations are summarized in table 1.Aggregate Properties FF FFFRadius of gyration (A˚) 9.48±0.41 9.25±0.30Volume (A˚3) 3495.77±14.53 3422.04±13.28Density (gr/ml) 1.779±0.007 1.782±0.006I1/I2, I1/I3, I2/I3 0.76±0.12, 0.66±0.10, 0.88±0.06 0.76±0.11, 0.66±0.09, 0.86±0.06PSA (%) 29.00±6.04 (42.18±1.44) 24.40±4.48 (34.64±3.41)I1, I2 and I3 are the principal moments of inertia of the aggregate. PSA is the polar accessible surface area.The numbers in parentheses correspond to the average PSA of FF and FFF monomers, computed by independentmonomer simulations17 .Table 1. Geometrical characteristics of FF and FFF aggregates at 300 K.394The FF and FFF aggregates have similar shapes (indicated by the comparablemoment-of-inertia ratios) and densities. The radius of gyration of the FFF aggregate hasa somewhat smaller mean and standard deviation (sd), reflecting the fact that the FFFaggregate is somewhat more stable. In line with this observation, the radius of gyrationof the FF aggregate increases faster with temperature17. The solvent-accessible surfacearea of the FF and FFF peptides has a mixed character, due to the non-polar sidechainsand the polar (charged) terminal ends and interior peptide bonds. The average fraction ofthe FF and FFF peptide polar solvent accessible surface area (PSA) is 42.2% and 34.6%,respectively, at 300 K, as computed by simulations of the FF and FFF monomers (with thesame implicit model GBSW13, 14). The PSA ratio is reduced in the FF and FFF aggregates,reflecting the fact that the polar groups participate in several interactions. Indeed, thepeptides form network structures in the aggregates, as we analyze below.Network Structures: The backbone moieties of several (2-6) adjacent peptides are fre-quently arranged into open or closed (ring-like) linear networks, in which adjacent pep-tides interact by head (NH3+)-to-tail (−OOC) hydrogen bonds and the aromatic planesof interacting sidechains are mainly oriented perpendicular to each other. A typical, six-peptides ring of the FF simulations is shown in fig. 1, along with the hexagonal ring patternobserved in the L-Phe-L-Phe crystals4. The open networks are more frequent due to en-tropic reasons; nevertheless, the closed networks are more stable energetically, due to bothnon-polar and polar interactions17. The network propensity is higher in the FFF solution.Energetic analysis shows that the non-polar and electrostatic interactions are stronger in thenetworks of the FFF aggregate17; this is in accord with the higher network propensity andthe higher stability of the FFF aggregate. The frequency of the peptide networks decreaseswith temperature, in agreement with the increase in the radius of gyration and the loss ofstability17.Figure 1. Left: The hexagonal ring network observed in FF crystals4 . Right: A typical, six-peptides ring network,observed in the FF simulations.3954 Concluding RemarksWe have investigated the conformational properties of aqueous FF and FFF solutions byimplicit-solvent Replica Exchange MD simulations. In both solutions, the peptides formstable ellipsoidal aggregates. Within the aggregates the peptides are arranged into open andclosed linear networks, which are stabilized by head-to-tail and sidechain interactions andhave some of the structural features observed in the FF crystals4. The intermolecular inter-actions are stronger in the FFF system, in line with the higher frequency of inter-peptidenetworks and the increased stability of the FFF aggregate in the temperature range of thesimulations. An energetic analysis shows that the side chains contribute to the aggregatestability by forming direct interactions and by modulating the screening of the terminielectrostatic interactions by solvent.References1. S. Gilead and E. Gazit, Supramolecular Chemistry 17, 2005, 87-92.2. E. Gazit, Chem. Soc. Rev. 36, 2007, 1263-1269.3. K. Chockalingam, M. Blenner and S. Banta. Protein Engineering, Design & Selection20, 2007, 155-161.4. C. H. Gorbitz, Chem. Commun. 2006, 2332-2334.5. N. Kol, L. Adler-Abramovich, D. Barlam, R. Z. Shneck, E. Gazit and I. Rousso. NanoLett. 5, 2005, 1343–1346.6. M. Reches and E. Gazit. Science 300, 2003, 625-628.7. M. Reches and E. Gazit, Nat. Nanotechnol. 1, 2006, 195-200.8. A. Mahler, M. Reches, M. Rechter, S. Cohen and E. Gazit. Adv. Mater. 18, 2006,1365-1370.9. M. Reches and E. Gazit. Isr. J. Chem. 45, 2005, 363-371.10. B.R. Brooks et al. J. Comput. Chem. 4, 1983, 187-217.11. N. Foloppe, A. D. MacKerell Jr. J. Comp. Chem. 21, 2000, 86-104.12. N. Foloppe, A. D. MacKerell Jr. J. Comp. Chem. 21, 2000, 105-120.13. J. Chen, W. Im, and C. L. Brooks III. J. Am. Chem.Soc. 128, 2006, 3728-3736.14. W. Im, J. Chen, and C. L. Brooks III. Adv. Prot. Chem. 2006, 72, 171-195.15. K. Hukushima and K. Nemoto. J. Phys. Soc. Jpn. 65, 1996, 1604-1608.16. K.Y. Sanbonmatsu and A.E. Garcia. Proteins 2, 2002, 46, 225-234.17. P. Tamamis, G. Archontis. L. Adler-Abramovich and E. Gazit. Paper in preparation.396

Insights into the Self-Assembly of Phenylalanine Oligopeptides by Replica Exchange MD Simulations with the GBSW Implicit-Solvent Model

http://juser.fz-juelich.de/record/153075/files/FZJ-2014-02748.pdf

Insights into the Self-Assembly of Phenylalanine Oligopeptides by Replica Exchange MD Simulations with the GBSW Implicit-Solvent Model

Abstract

Similar works

Full text

Available Versions

Juelich Shared Electronic Resources