Flexibility of Dicer Studied by Implicit Solvent Molecular Dynamics Simulations
Sarzyńska Joanna 1*, Mickiewicz Agnieszka 1, Miłostan Maciej 2, Łukasiak Piotr 1,2, Błażewicz Jacek 1,2, Figlerowicz Marek 1,1*, Kuliński Tadeusz
1Institute of Bioorganic Chemistry, Polish Academy of Sciences
ul. Noskowskiego 12/14, 61-704 Poznań, Poland
*e-mail: {joanna.sarzynska/tadeusz.kulinski}@ibch.poznan.pl
2Institute of Computing Sciences, Poznan University of Techonology
ul. Piotrowo 2, 60-965 Poznań, Poland
Received:
Received: 14 December 2009; revised: 2 March 2010; accepted: 10 March 2010; published online: 19 May 2010
DOI: 10.12921/cmst.2010.16.01.97-104
OAI: oai:lib.psnc.pl:717
Abstract:
Dicer is an enzyme responsible for processing double-stranded RNAs and plays a key role in an RNAi mechanism. Structural insight into the Dicer is provided by the crystal structure of eukaryotic Dicer from Giardia intestinalis. It has been proposed that the structure has three structurally rigid regions that are connected by the flexible hinges. Flexibility of the Dicer is believed to be a critical feature for its function. Spatial arrangement of the RNA-recognition and the catalytic regions is crucial for producing small RNAs of defined length. It has been suggested that in the Giardia Dicer a Platform domain may help in specific arrangement of these regions. To learn more about the role of the Platform domain in Giardia Dicer, we have performed molecular dynamics (MD) simulations of the whole Dicer (WT Dicer) and the
Dicer with a deleted platform domain (ΔPlf Dicer). The MD simulations were carried out in an implicit solvent model with two implementations of analytic Generalized Born (GB) solvation model in CHARMM: GBMV (Generalized Born using Molecular Volume) and GBSW (Generalized Born with simple Switching). To detect the key global motions of the Dicer, a principal component analysis (PCA) of the obtained MD trajectories has been used. To further explore the motion of the Dicer, we performed a domain motion analysis with the DYNDOM program. The simulations show that both WT Dicer and ΔPlf Dicer display flexibility which can be described as a movement of two or three domains. The removal of the Platform substantially changed the flexibility and arrangement of these domains. During the MD simulations of ΔPlf Dicer an large movement of the RNA-recognition domain was observed.
Key words:
domain motions, Giardia Dicer, implicit solvent model, molecular dynamics, principal component analysis
References:
[1] I.J. MacRae, K. Zhou, F. Li, A. Repic, A.N. Brooks, W.Z. Cande, P.D. Adams, J.A. Doudna, Structural Basis for Double-Stranded RNA Processing by Dicer, Science 311,195- 198 (2006).
[2] I.J. MacRae, K. Zhou, J.A. Doudna, Structural Determinants of RNA Recognition and Cleavage by Dicer. Nat. Struct. Mol. Biol. 14, 934-940 (2007).
[3] I.J. MacRae, F. Li, K. Zhou, W.Z. Cande, J.A. Doudna, Structure of Dicer and Mechanistic Implications for RNAi. Cold Spring Harb. Symp. Quant. Biol. 71, 73-80 (2006).
[4] M. Dlakic, DUF283 Domain of Dicer Proteins Has a Double-Stranded RNA-Binding Fold. Bioinformatics 22, 2711-2714 (2006).
[5] H.T. Allawi, M.W. Kaiser, A.V. Onufriev, W.P. Ma, A.E. Brogaard, D.A. Case, B.P. Neri, V.I. Lyamichev, Modeling of Flap Endonuclease Interactions With DNA Substrate. Journal of Molecular Biology 328, 537-554 (2003).
[6] J. Chocholousova, M. Feig, Implicit Solvent Simulations of DNA and DNA-Protein Complexes: Agreement with Explicit Solvent Vs Experiment, Journal of Physical Chemistry B 110, 17240-17251 (2006).
[7] V. Hornak, A. Okur, R.C. Rizzo, C. Simmerling, HIV-1 Protease Flaps Spontaneously Open and Reclose in Molecular Dynamics Simulations. Proceedings of the National Academy of Sciences of the United States of America 103, 915-920 (2006).
[8] M.S. Lee, F.R. Salsbury, C.L. Brooks, Novel Generalized Born Methods. Journal of Chemical Physics 116, 10606-10614 (2002).
[9] M.S. Lee, M. Feig, F.R. Salsbury, Jr., C.L. Brooks, III, New Analytic Approximation to the Standard Molecular Volume Definition and Its Application to Generalized Born Calculations. J. Comput. Chem. 24, 1348-1356 (2003).
[10] W. Im, M.S. Lee, C.L. Brooks, III, Generalized Born Model With a Simple Smoothing Function. J. Comput. Chem. 24, 1691-1702 (2003).
[11] J. Chen, W. Im, C. L. Brooks, III, Balancing Solvation and Intramolecular Interactions: Toward a Consistent Generalized Born Force Field. J. Am. Chem. Soc. 128, 3728-3736
(2006).
[12] A. Sali, T.L. Blundell, Comparative Protein Modelling by Satisfaction of Spatial Restraints, J. Mol. Biol. 234, 779-815 (1993).
[13] B.R. Brooks, R.E. Bruccoleri, B.D. Olafson, D.J. States, S. Swaminathan, M. Karplus, CHARMM: A Program for Macromolecular Energy, Minimization, and Dynamics Calculations.
J. Comp. Chem. 4, 187-217 (1983).
[14] B.R. Brooks, C. L. Brooks, A. D. Mackerell, L. Nilsson, R. J. Petrella, B. Roux, Y. Won, G. Archontis, C. Bartels, S. Boresch, A. Caflisch, L. Caves, Q. Cui, A.R. Dinner,
M. Feig, S. Fischer, J. Gao, M. Hodoscek, W. Im, K. Kuczera, T. Lazaridis, J. Ma, V. Ovchinnikov, E. Paci, R.W. Pastor, C.B. Post, J.Z. Pu, M. Schaefer, B. Tidor, R. M. Venable,
H. L. Woodcock, X. Wu, W. Yang, D.M. York, M. Karplus, CHARMM: The Biomolecular Simulation Program. Journal of Computational Chemistry 30, 1545-1614 (2009).
[15] A.D. MacKerell, D. Bashford, M. Bellott, R.L. Dunbrack, J. D. Evanseck, M.J. Field, S. Fischer, J. Gao, H. Guo, S. Ha, D. Joseph-McCarthy, L. Kuchnir, K. Kuczera, F.T. K. Lau, C. Mattos, S. Michnick, T. Ngo, D.T. Nguyen, B. Prodhom, W.E. Reiher, B. Roux, M. Schlenkrich, J.C. Smith, R. Stote, J. Straub, M. Watanabe, J. Wiorkiewicz-Kuczera, D. Yin, M. Karplus, All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins. Journal of Physical Chemistry B 102, 3586-3616 (1998).
[16] A.D. Mackerell, Jr., M. Feig, C.L. Brooks, III, Improved Treatment of the Protein Backbone in Empirical Force Fields. J. Am. Chem. Soc. 126, 698-699 (2004).
[17] M. Nina, D. Beglov, B. Roux, Atomic Radii for Continuum Electrostatics Calculations Based on Molecular Dynamics Free Energy Simulations. Journal of Physical Chemistry B 101, 5239-5248 (1997).
[18] J. Ryckaert, G. Ciccotti, H.J.C. Berendsen, Numerical Integration of the Cartesian Equations of Motion of a System With Constraints: Molecular Dynamics of N-Alkanes. J. Comp. Phys. 23, 327-341 (1977).
[19] D. Van der Spoel, E. Lindahl, B. Hess, G. Groenhof, A.E. Mark, H.J.C. Berendsen, GROMACS: Fast, Flexible, and Free. Journal of Computational Chemistry 26, 1701-1718 (2005).
[20] J. Mongan, Interactive Essential Dynamics. Journal of Computer-Aided Molecular Design 18, 433-436 (2004).
[21] W. Humphrey, A. Dalke, K. Schulten, VMD: Visual Molecular Dynamics, Journal of Molecular Graphics 14, 33-& (1996).
[22] S. Haider, G.N. Parkinson, S. Neidle, Molecular Dynamics and Principal Components Analysis of Human Telomeric Quadruplex Multimers. Biophysical Journal 95, 296-311 (2008).
[23] S. Hayward, A. Kitao, H.J. Berendsen, Model-Free Methods of Analyzing Domain Motions in Proteins From Simulation: a Comparison of Normal Mode Analysis and Molecular Dynamics Simulation of Lysozyme. Proteins 27, 425-437 (1997).
[24] S. Hayward, H.J. Berendsen, Systematic Analysis of Domain Motions in Proteins From Conformational Change: New Results on Citrate Synthase and T4 Lysozyme. Proteins 30, 144-154 (1998).
Dicer is an enzyme responsible for processing double-stranded RNAs and plays a key role in an RNAi mechanism. Structural insight into the Dicer is provided by the crystal structure of eukaryotic Dicer from Giardia intestinalis. It has been proposed that the structure has three structurally rigid regions that are connected by the flexible hinges. Flexibility of the Dicer is believed to be a critical feature for its function. Spatial arrangement of the RNA-recognition and the catalytic regions is crucial for producing small RNAs of defined length. It has been suggested that in the Giardia Dicer a Platform domain may help in specific arrangement of these regions. To learn more about the role of the Platform domain in Giardia Dicer, we have performed molecular dynamics (MD) simulations of the whole Dicer (WT Dicer) and the
Dicer with a deleted platform domain (ΔPlf Dicer). The MD simulations were carried out in an implicit solvent model with two implementations of analytic Generalized Born (GB) solvation model in CHARMM: GBMV (Generalized Born using Molecular Volume) and GBSW (Generalized Born with simple Switching). To detect the key global motions of the Dicer, a principal component analysis (PCA) of the obtained MD trajectories has been used. To further explore the motion of the Dicer, we performed a domain motion analysis with the DYNDOM program. The simulations show that both WT Dicer and ΔPlf Dicer display flexibility which can be described as a movement of two or three domains. The removal of the Platform substantially changed the flexibility and arrangement of these domains. During the MD simulations of ΔPlf Dicer an large movement of the RNA-recognition domain was observed.
Key words:
domain motions, Giardia Dicer, implicit solvent model, molecular dynamics, principal component analysis
References:
[1] I.J. MacRae, K. Zhou, F. Li, A. Repic, A.N. Brooks, W.Z. Cande, P.D. Adams, J.A. Doudna, Structural Basis for Double-Stranded RNA Processing by Dicer, Science 311,195- 198 (2006).
[2] I.J. MacRae, K. Zhou, J.A. Doudna, Structural Determinants of RNA Recognition and Cleavage by Dicer. Nat. Struct. Mol. Biol. 14, 934-940 (2007).
[3] I.J. MacRae, F. Li, K. Zhou, W.Z. Cande, J.A. Doudna, Structure of Dicer and Mechanistic Implications for RNAi. Cold Spring Harb. Symp. Quant. Biol. 71, 73-80 (2006).
[4] M. Dlakic, DUF283 Domain of Dicer Proteins Has a Double-Stranded RNA-Binding Fold. Bioinformatics 22, 2711-2714 (2006).
[5] H.T. Allawi, M.W. Kaiser, A.V. Onufriev, W.P. Ma, A.E. Brogaard, D.A. Case, B.P. Neri, V.I. Lyamichev, Modeling of Flap Endonuclease Interactions With DNA Substrate. Journal of Molecular Biology 328, 537-554 (2003).
[6] J. Chocholousova, M. Feig, Implicit Solvent Simulations of DNA and DNA-Protein Complexes: Agreement with Explicit Solvent Vs Experiment, Journal of Physical Chemistry B 110, 17240-17251 (2006).
[7] V. Hornak, A. Okur, R.C. Rizzo, C. Simmerling, HIV-1 Protease Flaps Spontaneously Open and Reclose in Molecular Dynamics Simulations. Proceedings of the National Academy of Sciences of the United States of America 103, 915-920 (2006).
[8] M.S. Lee, F.R. Salsbury, C.L. Brooks, Novel Generalized Born Methods. Journal of Chemical Physics 116, 10606-10614 (2002).
[9] M.S. Lee, M. Feig, F.R. Salsbury, Jr., C.L. Brooks, III, New Analytic Approximation to the Standard Molecular Volume Definition and Its Application to Generalized Born Calculations. J. Comput. Chem. 24, 1348-1356 (2003).
[10] W. Im, M.S. Lee, C.L. Brooks, III, Generalized Born Model With a Simple Smoothing Function. J. Comput. Chem. 24, 1691-1702 (2003).
[11] J. Chen, W. Im, C. L. Brooks, III, Balancing Solvation and Intramolecular Interactions: Toward a Consistent Generalized Born Force Field. J. Am. Chem. Soc. 128, 3728-3736
(2006).
[12] A. Sali, T.L. Blundell, Comparative Protein Modelling by Satisfaction of Spatial Restraints, J. Mol. Biol. 234, 779-815 (1993).
[13] B.R. Brooks, R.E. Bruccoleri, B.D. Olafson, D.J. States, S. Swaminathan, M. Karplus, CHARMM: A Program for Macromolecular Energy, Minimization, and Dynamics Calculations.
J. Comp. Chem. 4, 187-217 (1983).
[14] B.R. Brooks, C. L. Brooks, A. D. Mackerell, L. Nilsson, R. J. Petrella, B. Roux, Y. Won, G. Archontis, C. Bartels, S. Boresch, A. Caflisch, L. Caves, Q. Cui, A.R. Dinner,
M. Feig, S. Fischer, J. Gao, M. Hodoscek, W. Im, K. Kuczera, T. Lazaridis, J. Ma, V. Ovchinnikov, E. Paci, R.W. Pastor, C.B. Post, J.Z. Pu, M. Schaefer, B. Tidor, R. M. Venable,
H. L. Woodcock, X. Wu, W. Yang, D.M. York, M. Karplus, CHARMM: The Biomolecular Simulation Program. Journal of Computational Chemistry 30, 1545-1614 (2009).
[15] A.D. MacKerell, D. Bashford, M. Bellott, R.L. Dunbrack, J. D. Evanseck, M.J. Field, S. Fischer, J. Gao, H. Guo, S. Ha, D. Joseph-McCarthy, L. Kuchnir, K. Kuczera, F.T. K. Lau, C. Mattos, S. Michnick, T. Ngo, D.T. Nguyen, B. Prodhom, W.E. Reiher, B. Roux, M. Schlenkrich, J.C. Smith, R. Stote, J. Straub, M. Watanabe, J. Wiorkiewicz-Kuczera, D. Yin, M. Karplus, All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins. Journal of Physical Chemistry B 102, 3586-3616 (1998).
[16] A.D. Mackerell, Jr., M. Feig, C.L. Brooks, III, Improved Treatment of the Protein Backbone in Empirical Force Fields. J. Am. Chem. Soc. 126, 698-699 (2004).
[17] M. Nina, D. Beglov, B. Roux, Atomic Radii for Continuum Electrostatics Calculations Based on Molecular Dynamics Free Energy Simulations. Journal of Physical Chemistry B 101, 5239-5248 (1997).
[18] J. Ryckaert, G. Ciccotti, H.J.C. Berendsen, Numerical Integration of the Cartesian Equations of Motion of a System With Constraints: Molecular Dynamics of N-Alkanes. J. Comp. Phys. 23, 327-341 (1977).
[19] D. Van der Spoel, E. Lindahl, B. Hess, G. Groenhof, A.E. Mark, H.J.C. Berendsen, GROMACS: Fast, Flexible, and Free. Journal of Computational Chemistry 26, 1701-1718 (2005).
[20] J. Mongan, Interactive Essential Dynamics. Journal of Computer-Aided Molecular Design 18, 433-436 (2004).
[21] W. Humphrey, A. Dalke, K. Schulten, VMD: Visual Molecular Dynamics, Journal of Molecular Graphics 14, 33-& (1996).
[22] S. Haider, G.N. Parkinson, S. Neidle, Molecular Dynamics and Principal Components Analysis of Human Telomeric Quadruplex Multimers. Biophysical Journal 95, 296-311 (2008).
[23] S. Hayward, A. Kitao, H.J. Berendsen, Model-Free Methods of Analyzing Domain Motions in Proteins From Simulation: a Comparison of Normal Mode Analysis and Molecular Dynamics Simulation of Lysozyme. Proteins 27, 425-437 (1997).
[24] S. Hayward, H.J. Berendsen, Systematic Analysis of Domain Motions in Proteins From Conformational Change: New Results on Citrate Synthase and T4 Lysozyme. Proteins 30, 144-154 (1998).
