Knecht, V.

Lipowsky, R.

Juelich Shared Electronic Resources

John von Neumann Institute for ComputingConformational Polymorphism of a FibrillogenicFusion Peptide in Explicit Solvent andat an InterfaceV. Knecht, R. Lipowskypublished 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. 109-112, 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/volume40Conformational Polymorphism of a Fibrillogenic FusionPeptide in Explicit Solvent and at an InterfaceVolker Knecht and Reinhard LipowskyMax Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, GermanyE-mail: vknecht@mpikg.mpg.deThe development of therapeutic agents against amyloid diseases requires an understanding ofthe conformational properties of fibrillogenic species on a microscopic level. Here we have usedmolecular dynamics simulations to study the fibrillogenic fusion peptide B18 in monomericform in various environments. In particular, our results indicate that B18 forms β-sheet/coilconformations in water, whereas adsorption at a water/vapor interface induces α-helical con-formations. α-β transition pathways in water are suggested. Our results show that previousspectroscopic measurements reflect properties of monomers and reveal a pronounced confor-mational polymorphism of B18 in different environments, thus highlighting the need for anexplicit description of the solvent environment in order to understand fibrillogenic species frommolecular dynamics simulations.1 IntroductionA number of neurodegenerative diseases such as Alzheimer’s are associated with the con-version of proteins from a soluble, functional form into a β-rich structure that is highlyprone to aggregate into toxic oligomers or so-called amyloid fibrils. The conformationaltransition is believed to take place in a partially denaturing environment of a cellular com-partment either in solution or at an interface. Hence, the development of therapeutic agentsagainst amyloid diseases requires an understanding of the conformational polymorphismin different environments on a microscopic level. To study fibrillogenic species experi-mentally in atomic detail is difficult because of their tendency to aggregate. Therefore, anindispensable tool to study these systems is provided by computer simulations. Here wehave chosen the 18-residue peptide B18, a fragment of the sea-urchin fertilization proteinBindin1 as a model system. The amphiphilic sequence of the peptide is shown in Fig. 1 (a).B18 forms amyloid fibrils in vitro. The soluble form in water forms β-sheet and coil struc-tures with increased β-sheet content in the presence of NaCl as indicated from circulardichroism (CD) spectroscopy. Addition of trifluorethanol (TFE) or adsorption of B18 ata water/air interface induce α-helical conformations as indicated from CD or infrared re-flection absorption spectroscopy (IRRAS), respectively, the latter suggesting helices to beparallel to the interface.2, 3 Nuclear magnetic resonance (NMR) measurements indicate ahelix-kink-helix motif for B18 in water/TFE with 70:30 volume fractions2 as shown inFig. 1 (b). No detailed structure is available for B18 in pure water in the presence orabsence of NaCl or at a water/air interface. In fact, it is not even clear to which extent con-formations indicated from CD or IRRAS arise from mono- or oligomers. We have usedmolecular dynamics (MD) simulations to study B18 in monomeric form in explicit solventand interfacial environments on a microscopic level.4109(a) (b)CNFigure 1. (a) Amino acid sequence and (b) structural model for B18 in a water/TFE 70:30 (volume fractions) mix-ture based on NMR data2 in ribbon representation. The color code distinguishes between hydrophobic (yellow)and hydrophilic (blue, green, and red) residues.water 1initial water 3 water/vaporwater 2Figure 2. Initial configuration (“initial”), typical β-sheet conformations of B18 in water (“water 1 – 3”), andrepresentative conformation at a water/vapor interface (“water/vapor”). The representation is similar to thatchosen in Fig. 1 (b). In “water/vapor”, positions of water oxygens are indicated as gray dots.2 MethodsB18 in explicit water/TFE with 70:30 volume fractions, pure water in absence and presenceof 100 mM NaCl, and at a water/vapor interface with vapor modeling air were studied usingperiodic boundary conditions. Initial peptide configurations were a helix-kink-helix as inFig. 1 (b), an extended as in Fig. 2 (initial) or a β-sheet/coil conformation as in Fig. 2 (wa-ter 3). Typically, three 50 ns simulations using the same initial peptide configuration, butdifferent sets of initial velocities were performed. Most simulations were carried out at293 K to mimic experimental conditions. Simulation details are given elsewhere.43 Results and DiscussionB18 in water/TFE with 70:30 volume fractions, pure water in the absence or presenceof 100 mM NaCl, and at a water/vapor interface with vapor modeling air were studied.During simulations started from extended peptide configurations as in Fig. 2 (initial), coiland β-sheet conformations as in Fig. 2 (water 1 – 3) were adopted. β-sheets were mainlyformed by hydrophobic residues, see Fig. 2 (water 1 – 3) (yellow). Addition of NaCl led toan increase in the average β-sheet content. Various β-sheets containing different residueswere observed. β-sheets formed twice in independent simulations, suggesting that they aretypical structures in water, are shown in Fig. 2 (water 1 – 3).Pre-formed α-helical conformations as in Fig. 1 (b) were more stable in water/TFE orat a water/vapor interface than in pure water. In general, α-helical conformations weremore stable in the C-terminal than the N-terminal half of the peptide. In water at 350 K,transitions from α-helical into β-sheet conformations where observed as shown in Fig. 3.110NCFigure 3. α-β transitions of B18 in water at 350 K. The representation is similar to that chosen in Fig. 1.The C-terminal and, after 7 ns, the N-terminal helix dissolved in two independent simula-tions. Thereafter, the peptide underwent a transition from a compact coil as in Fig. 3 (7 ns)to more extended β-sheet conformations, see Fig. 3 (31 – 37 ns). The occurrence of a com-pact coil intermediate is similar to what has been observed during α-β transitions of othersequences in previous simulations, see references in4, suggesting a universal feature forα-β transitions.A peptide in β-sheet/coil conformation as in Fig. 2 (water 3) placed next to a wa-ter/vapor interface was spontaneously adsorbed at the interface. At the interface, theamount of β conformations decreased, and α-helical conformations formed in the C-terminal half of the peptide in two out of three simulations (compare Fig. 2 (water/vapor)and Fig. 1), suggesting early conformational transitions after adsorption. In all simulationsof B18 at water/vapor interfaces, α-helical segments were approximately parallel to theinterface.4 ConclusionOur results on the conformation of monomeric B18 in water and at a water/vapor interfaceand the interfacial orientation of the peptide are in agreement with available spectroscopicdata and, thus, indicate these data to reflect properties of monomers. In addition, oursimulations give insights into conformational distributions and transition pathways on amicroscopic level. Revealing a pronounced conformational polymorphism of B18 in dif-ferent environments, our work highlights the need for an explicit description of the solventenvironment in order to understand fibrillogenic species from MD simulations.References1. A. S. Ulrich, M. Otter, C. G. Glabe, and D. Hoekstra, J. Biol. Chem. 273, 16748(1998).2. R. W. Glaser, M. Grune, C. Wandelt, and A. S. Ulrich, Biochemistry 38, 2560 (1999).3. E. Maltseva, Model membrane interactions with ions and peptides at the air/waterinterface, Ph.D. thesis, Universita¨t Potsdam (2005).4. V. Knecht, H. Mo¨hwald, and R. Lipowsky, J. Phys. Chem. B 111, 4161 (2007).111

Conformational Polymorphism of a Fibrillogenic Fusion Peptide in Explicit Solvent and at an Interface

http://juser.fz-juelich.de/record/153007/files/FZJ-2014-02676.pdf

Conformational Polymorphism of a Fibrillogenic Fusion Peptide in Explicit Solvent and at an Interface

Abstract

Similar works

Full text

Available Versions

Juelich Shared Electronic Resources