Kurkal-Siebert, V.

Langowski, J.

Smith, J. C.

Tozzini, V.

Trylska, J.

Voltz, K.

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John von Neumann Institute for ComputingGlobal Motions in the Nucleosome ExploredUsing a Coarse-Grained ModelK. Voltz, J. Trylska, V. Tozzini, V. Kurkal-Siebert,J. C. Smith, J. Langowskipublished 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. 141-144, 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/volume40Global Motions in the Nucleosome Explored Using aCoarse-Grained ModelKarine Voltz1,2, Joanna Trylska3, Valentina Tozzini4, Vandana Kurkal-Siebert5,Jeremy C. Smith2,6, and Joerg Langowski11 Biophysics of Macromolecules, German Cancer Research Center, Heidelberg, Germany2 Computational Molecular Biophysics, IWR, University of Heidelberg, GermanyE-mail: Karine.Voltz@iwr.uni-heidelberg.de3 Interdisciplinary Center for Mathematical and Computational Modelling, University of Warsaw,Warsaw, Poland4 NEST-INFM-Scuola Normale Superiore, Pisa, Italy5 Molecular Modelling, Polymer Physics, BASF Aktiengesellschaft, Ludwigshafen, Germany6 Center for Molecular Biophysics, Oak Ridge National Laboratory, USAThe nucleosome is the basic compacting unit of chromatin, a complex structure that enablesDNA to fit in the eucaryotic cell nucleus. Because many biological processes require free DNAas a substrate, the nucleosome has to undergo conformational transitions to allow the DNAtarget sites to be exposed. To obtain insight into the global dynamics of the nucleosome, mi-crosecond timescale coarse-grained molecular dynamics is performed. Here we report a princi-pal component analysis (PCA) realised on a 5µs coarse-grained molecular dynamics trajectoryto identify the global motions obtained in the nucleosome.1 IntroductionIn the nucleosome, 147-bp DNA are wrapped almost twice around a protein core consist-ing of eight histone proteins, one tetramer H3-H4 and two dimers H2A-H2B. The histoneprotein core, composed mainly of α-helices, is very stable in contrast to the non-structuredhistone N-terminal tails, that pass between the DNA superhelix turns. Despite the highnumber of interactions between nucleosomal DNA and the surface of the protein core,nucleosomal DNA can become free to be processed by DNA binding proteins involved inDNA transcription, replication, recombination or repair. The mechanisms underlying DNAtarget site exposure are still under debate. One proposed mechanism, based on single-nucleosome FRET evidence, postulates that significant pieces of nucleosomal DNA (upto 70 bp) can transiently detach from the protein core1, 2. These reversible conformationalchanges, believed to occur on the 50-250 ms timescale, could be responsible for the pro-gressive invasion of the nucleosome by DNA-binding proteins.To characterize the conformational transitions leading to DNA accessibility, it is im-portant to understand nucleosome dynamics at equilibrium and on a long timescale. Forthis purpose, we performed coarse-grained (CG) molecular dynamics (MD) simulationsusing a model specifically developed for the nucleosome3. Classical all-atom MD of largesystems such as the nucleosome is currently limited to about 100 nanosecond timescale,while with the present model of the nucleosome, a one-bead representation together withthe absence of explicit water, MD simulations of the nucleosome can be carried out over141Figure 1. All-atom and coarse-grained representation of the nucleosome (structure 1KX5). The residues arerepresented by single spherical beads centered on α-carbon for amino acids and on phosphorus for nucleic acids.The histones and the DNA are represented in different colors. The nucleosome is symmetric with respect to theso-called dyad axis.several microseconds. In the present proceedings, after briefly presenting the CG model,we report a principal component analysis (PCA) performed on a 5µs CG MD trajectoryenabling the identification of slow collective motions in the nucleosome.2 MethodA detailed description of the CG model and its force-field parameterization is reported ina previous study3. In this CG model, protein residues and DNA nucleotides are repre-sented as single beads (Figure 1) interacting through harmonic (for neighboring) or Morse(for nonbonded) potentials which depend on the interbead distances. This model sharessimilarity with Gaussian network models (GNM) but, in contrast to GNM, the Morse de-scription of nonbonded interactions allows realistic anharmonic dynamics of the system.Force-field parameters were estimated by Boltzmann inversion of the corresponding radialdistribution functions computed from a reference 5-ns all-atom MD simulation and furtherrefined to obtain agreement with all-atom MD root-mean-square fluctuations (RMSF).Coarse-grained MD simulations were performed using the DL POLY package5. Thestarting structure used was the 1KX5 structure4 energy-minimized in solvent using the142Charmm627 all-atom force-field. A Langevin bath was used to account for the frictionaland stochastic effects of the solvent. The reduction of the system allowed us to apply a20-fs timestep. The simulation was carried out at 300 K during 5 µs.Principal component analysis, also called essential dynamics analysis7, provides a wayto identify the most significant directions of motions in the system. The method consistsin diagonalizing the symmetric 3N×3N covariance matrix derived from the MD trajectory,whose elements are defined as Cij = 〈(xi − 〈xi〉)(xj − 〈xj〉)〉 where xi and xj are theCartesian coordinates of the atom i and j. The resulting eigenvectors give the direction andtheir corresponding eigenvalues quantify the magnitude of the fluctuations. Eigenvectorswith the highest eigenvalues are called the principal components or principal modes. Here,PCA was performed with the GROMACS package on a 5-µ CG MD trajectory. The tailswere excluded from the analysis since their high mobility masked the motion of the DNAand the protein core.2.1 Results and DiscussionFigure 2. Global motions of the nucleosome. A and a: initial nucleosome 1KX5 structure. B–D and b–d:nucleosome conformations deformed along the first three modes. Each residue is colored with respect to its root-mean-squared fluctuation (RMSF) along the mode; blue and red correspond to low and high RMSFs, respectively.Figure 2 shows the directions of the motions for the first three principal components.Residues are colored with respect to their RMSF along each eigenvector. The ten eigen-vectors with the largest eigenvalues describe 22 % of the total protein motion, a smallerfraction than what is usually observed for other systems such as proteins. This result maybe the consequence that important structural transitions in the nucleosome occur on a largertimescale than 5µs.The motion along the first mode corresponds to a bending out of the plane of the nu-cleosome that mostly involves i) both extremities (ten basepairs) of the DNA superhelix;ii) the facing DNA stretches located on the respective opposite turn; and iii) amino acids ofH3, H3’, H4 and H4’ interacting with these regions. Simultaneously to the bending of this143region, several residues centered around the dyad axis (i.e., ≈10-bp of DNA and residuesfrom H3 and H3’) translate in the opposite direction to the out-of-plane bending motion.The most rigid regions along this mode are residues that belong to the histones H2B andthe DNA basepairs interacting with them.The second principal component describes a rocking motion center of which is locatedon the dyad axis. As in the first mode, this mostly involves both extremities of the DNAsuperhelix, the facing DNA stretches located on the respective opposite turn, and aminoacids interacting with these regions, while histones H2B and interacting DNA residuescontribute less to this motion.Finally, the third principal mode, represents a deformation of the nucleosome in theplane of the nucleosome. In this motion, the DNA superhelix extremities and amino acidsinteracting with these regions participate in the stretching of the nucleosome in a directionperpendicular to the dyad axis while H2B residues and the DNA part interacting with themcontributes to stretching the nucleosome in the direction of the dyad axis.3 OutlookFurther work is ongoing to investigate, in particular, the spontaneous unwrapping of nu-cleosomal DNA extremities from the nucleosome protein core. We also plan to study theinteractions between several nucleosomes in a nucleosomal array within the context of thechromatin fiber.References1. G. Li, M. Levitus, C. Bustamante and J. Widom, Rapid spontaneous accessibility ofnucleosomal DNA Nat. Struc. Mol. Biol. 12, 46–53, 2005.2. M. Tomschik, H. Zheng, K. van Holde, J. Zlatanova, S. H. and Leuba, Fast, long-range, reversible conformational fluctuations in nucleosomes revealed by single-pairfluorescence resonance energy transfer Proc. Natl. Acad. Sci. U.S.A. 102, 3278–3283,2005.3. K. Voltz, J. Trylska, V. Tozzini, V. Kurkal-Siebert, J. Langowski and J. Smith, Coarse-grained force field for the nucleosome from self-consistent multiscaling J. Comput.Chem. 29, 1429–1439, 2008.4. C. A. Davey, D. F. Sargent, K. Luger, A. W. Maeder and T. J. Richmond, Solventmediated interactions in the structure of the nucleosome core particle at 1.9A˚ J. Mol.Biol. 319, 1097–1113, 2002.5. W. Smith, T. R. Forester, DLPOLY2.0: A general-purpose parallel molecular dynam-ics simulation package J. Mol. Graph. 14, 136–141, 1996.6. Jr. A.D. MacKerell, N. Banavali, and N. Foloppe, Development and current status ofthe CHARMM force field for nucleic acids Biopolymers 56, 257–265, 2001.7. A. Amadei, A. B. M. Linssen, H. J. C. Berendsen Essential dynamics of proteinsProteins 17, 412-425, 1993.144

Global Motions in the Nucleosome Explored Using a Coarse-Grained Model

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Global Motions in the Nucleosome Explored Using a Coarse-Grained Model

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