Mechanical Model of DNA Allostery - American Chemical Society

Letter pubs.acs.org/JPCL

Mechanical Model of DNA Allostery Tomás ̌ Dršata,†,‡ Marie Zgarbová,§ Naďa Špačková,∥,⊥ Petr Jurečka,§ Jiří Šponer,∥,# and Filip Lankaš*,† †

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague, Czech Republic ‡ Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University Prague, Albertov 6, 128 43 Prague, Czech Republic § Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 771 46 Olomouc, Czech Republic ∥ Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 612 65 Brno, Czech Republic ⊥ Department of Condensed Matter Physics, Faculty of Science, Masaryk University, Kotlárš ká 2, 611 37 Brno, Czech Republic # CEITEC − Central European Institute of Technology, Campus Bohunice, Kamenice 5, 625 00 Brno, Czech Republic S Supporting Information *

ABSTRACT: The importance of allosteric effects in DNA is becoming increasingly appreciated, but the underlying mechanisms remain poorly understood. In this work, we propose a general modeling framework to study DNA allostery. We describe DNA in a coarse-grained manner by intra-base pair and base pair step coordinates, complemented by groove widths. Quadratic deformation energy is assumed, yielding linear relations between the constraints and their effect. Model parameters are inferred from standard unrestrained, explicit-solvent molecular dynamics simulations of naked DNA. We applied the approach to study minor groove binding of diamidines and pyrrole−imidazole polyamides. The predicted DNA bending is in quantitative agreement with experiment and suggests that diamidine binding to the alternating TA sequence brings the DNA closer to the A-tract conformation, with potentially important functional consequences. The approach can be readily applied to other allosteric effects in DNA and generalized to model allostery in various molecular systems. SECTION: Biophysical Chemistry and Biomolecules

A

quantify their effect on DNA conformation. Crystal structures are difficult to obtain and may be affected by packing forces; solution experiments do not provide detailed structural information. Thus, computational methods may be a viable choice. A range of methods have been employed, from quantum chemical calculations through molecular modeling to QSAR approaches.11 In particular, atomistic molecular dynamics (MD)12−15 and flexible docking16 provide a highresolution picture of the complex but may be computationally intensive and may need special parametrization of the ligand and its interactions. In this work, we propose a different approach to investigate allosteric effects in DNA. In our model, a DNA oligomer is described by a reduced set of internal coordinates, namely, an intra-base pair coordinate buckle, propeller, opening, shear, stretch and stagger, an inter-base pair or step coordinate tilt, roll, twist, shift, slide, and rise, as well as minor and major groove widths. The deformation energy, that is, the free energy needed to distort DNA from its equilibrium conformation, is assumed to be a general quadratic function of the coordinates.

llosteric mechanisms in proteins have been extensively studied,1 and it has been increasingly appreciated that DNA is allosteric, too.2 In the context of DNA, allosteric effects are commonly understood to involve conformational changes due to an initial binding event that alters the affinities of subsequent binding events.2 It is not necessary that two separate energy minima be involved; rather, a suitable shift of the three-dimensional structure due to the initial binding may produce the effect. For instance, binding into the minor groove affects interactions in the obverse major groove, where the ligand is not in direct contact with the minor groove binder.3 Additional changes due to minor groove binding, such as induced DNA bending, may result in subsequent disruption of a protein−DNA binding interface.4 More distal effects (over several helical turns) have recently been reported.5 A prominent class of DNA allosteric effectors is minor groove binders such as pyrrole−imidazole (Py/Im) polyamides, promising antitumor drugs6 also designed, for example, to quantify protein indirect readout,3 inhibit DNA methylation,7 or detect DNA sequences in microarrays.8 Heterocyclic diamidines and related compounds are another important group of minor groove binders. They exhibit biological effects including clinical antiparasitic activity.9,10 To understand and optimize the action of minor groove binders, it is necessary to © 2014 American Chemical Society

Received: August 29, 2014 Accepted: October 17, 2014 Published: October 17, 2014 3831

dx.doi.org/10.1021/jz501826q | J. Phys. Chem. Lett. 2014, 5, 3831−3835

The Journal of Physical Chemistry Letters

Letter

Table 1. Sequences and Their Allosteric Properties sequence GCCTGGA6CTGTGC

code

binder

bending angle (°)a

A-tract netropsin

GCCTGG(TA)3CTGTGC

TA

GCGCC2AG2C2TG2GCGC

CD

GCCTGG(CG)3CTGTGC

CG

GCCTGG(mCG)3CTGTGC

mCG

netropsin polyamide polyamide polyamide

12 16 7 18 17 20 4 5 6 6

± ± ± ± ± ± ± ± ± ±

1 1 0 2 0 1 0 0 0 0

bending direction (°)a,b 200 191 359 180 360 360 355 357 2 2

± ± ± ± ± ± ± ± ± ±

1 0 7 2 1 1 4 2 4 2

deformation energy (kcal/mol)a 0 0.85 0 4.60 0 0.93 0 0.22 0 0.43

± 0.03 ± 0.02 ± 0.01 ± 0.02 ± 0.03

a

Errors are mean differences between values for the whole MD trajectory and for its halves. bA direction of 180° indicates bending toward the minor groove, and 0° (or 360°) means bending toward the major groove.

Figure 1. Allosteric effects of netropsin binding to the alternating TA sequence. Conformation of the naked, unconstrained DNA (blue) changes due to netropsin binding to the minor groove. The binding is modeled by constraining the minor groove width in the central five steps (red, black arrow). In response, the other coordinates change to minimize the deformation energy of the constrained system (red). The model predicts netropsin binding to cause major groove narrowing, decrease propeller and roll, and increase twist. This brings the alternating TA sequence in the complex closer to the conformation of an unconstrained A-tract (gray).

response if a subset of its coordinates is constrained. It is found that the changes of the free coordinates are linear functions of the imposed changes of the constrained coordinates. Detailed mathematical derivations are given in the Supporting Information (SI). To model the response to the ligand binding, therefore, one has to know the profile of the minor groove width in the DNA−ligand complex. We assume that the profile is dictated by the ligand itself and is independent of the DNA sequence. This may be a good approximation given the typically very tight binding of the ligand, fixed to the groove and further stabilized by the rearrangement of surrounding water molecules.21 DNA complexes with some ligands, such as netropsin, have been crystallized multiple times (see the SI), and a high-resolution crystal of a DNA−polyamide complex is also known.4 Chemically and sterically similar binders are assumed to impose similar minor groove widths. The allosteric effect of ligand binding manifests itself not only by DNA conformational changes but also by changes in DNA flexibility. Our model can predict changes in DNA flexibility upon constraining some of its coordinates. As the first application, we investigated binding of small ligands into the minor groove of an A-tract and an alternating TA sequence, studied earlier by Wilson and co-workers using gel electrophoresis.9,10 These authors found that the naked A-

The model thus has two sets of parameters: the equilibrium values of the coordinates (shape parameters) and the matrix of stiffness parameters, or stiffness matrix. The parameters are deduced from the first and second moments of the coordinate distribution in the canonical ensemble, using relations provided by the general theory of thermodynamic fluctuations.17 The ensemble, in turn, is approximated by coordinate snapshots from an atomic-resolution, unrestrained MD trajectory of the naked DNA molecule. Thus, one does not need to artificially distort the DNA; it is enough to observe fluctuations in unrestrained MD and deduce the model parameters from them. Explicit solvent, atomic-resolution MD simulations of naked DNA oligomers are now a standard task, with trajectory lengths routinely approaching 1 μs.18−20 Suppose that a ligand binding fixes minor groove widths at a particular location on the DNA. In general, the binders widen the minor groove (Py/Im polyamides) or narrow it (diamidines). Thus, due to ligand binding, a subset of the model coordinates (namely, certain minor groove widths) is constrained to prescribed, fixed values. How will the remaining free coordinates change? They will relax to values corresponding to the minimum of the deformation energy consistent with the constraint. Because the energy is a quadratic function of the coordinates, the minimum can be obtained analytically. Thus, the model can readily predict the DNA conformational 3832



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widths) necessarily limit the precision of our model. A comparison of our MD structures with predictions of a highthroughput model extensively tested for protein−DNA interactions 34 shows that both methods agree nearly quantitatively and can predict subtle structural variations such as the local maximum of twist and local minimum of roll in the middle of the CD sequence. Exact quantitative comparison is not possible due to different conformational analysis algorithms used (3DNA in our case). Finally, we modeled the polyamide binding to the alternating CG sequence, as in the methyltranferase inhibition experiments of Dervan and co-workers.7 We investigated a DNA oligomer with the central CGCGCG sequence (CG for short) and imposed the minor groove width from the CD crystal. The structural changes upon polyamide binding are small as the minor groove of the naked CG sequence is already wide. This is consistent with the critical effect of the N2 amino group on the minor groove width and other DNA properties.35,36 However, Dervan and co-workers hypothesize that the polyamide stabilizes the complex, disallowing the structural reorganization of the CpG substrate necessary for catalysis. To get insight into the issue, we computed how the imposed minor groove constraint changes the conformational entropy Sc associated with the remaining, unconstrained coordinates (see the SI). The decrease of TSc upon ligand binding (T = 300 K) is roughly 3 kcal/mol. A very similar value is also found for the other systems in Table 1. Methylating the central CG sequence (we used 5-mC parameters from earlier work35) in both strands (mCG) does not change the structural and flexibility effects of the polyamide binding very much. The model is by no means limited to assessing the effect of small-molecule binding into the minor groove. The binder can be any molecule, for example, a protein, as long as its conformational constraints imposed on the DNA are known. Also, there is nothing unique about groove widths in the model, and other coordinates may be constrained equally well. For instance, thermophilic organisms seem to keep their DNA overtwisted,37 which necessarily induces distortions in other coordinates through the allosteric mechanism. Our model is based on the relationship between the magnitude of fluctuations of thermodynamic variables and the underlying stiffness associated with these variables. This principle, provided by the general theory of fluctuations,17 was used earlier to deduce sequence-dependent DNA stiffness at the level of base pair steps38,39 or base pairs.40 Independently, rigid base or base pair DNA models have been proposed.41−43 The latter approach assumes a certain microscopic structure of the DNA, namely, that it consists of interacting rigid bodies representing bases or base pairs. In contrast, models using thermodynamic fluctuation theory do not assume any microstructure of the given system, just a set of fluctuating state variables that describe it. Thus, it is straightforward to add more variables as needed, such as the groove widths used here. By considering a suitable set of fluctuating coordinates, the approach can be generalized to investigate allostery in various molecular systems. On the other hand, the model depends on the quadratic deformation energy, which is a reasonable approximation for small deformations in DNA (although moderate anharmonic effects are present there as well33). A strongly anharmonic energy landscape is out of reach of the model. In summary, we propose a general modeling framework to study allosteric effects in DNA. The model assumes a quadratic

tract sequence is bent into the minor groove, whereas the naked TA is essentially straight, a fact reported earlier with consequences for protein−DNA binding.22−24 However, upon binding the antiparasitic diamidine DB75 and its variants, as well as netropsin, the A-tract bending changes relatively little, while the TA sequence becomes bent in much the same way as the A-tract. To model this situation, we performed unrestrained MD simulations of two DNA oligomers, one with an A6-tract in the middle and the other with the TATATA sequence (TA for short, Table 1). The oligomers were immersed in explicit water with KCl salt, the Amber ff99bsc0 force field25 was used, and trajectories were prolonged to 1 μs each. Time series of the internal coordinates were obtained using the 3DNA software.26 The simulation and data analysis protocol was described in detail earlier.27 The minor groove profile of the netropsin− DNA complex, averaged over five different crystals, was used as the model input (see the SI for details). Figure 1 shows the imposed minor groove width and the modeled conformational response of the TA sequence. Equilibrium values for the unconstrained simulated A-tract sequence are shown for comparison. It is seen that the ligand binding induces a narrower major groove, more negative propeller, lower roll, and higher twist. This brings the ligandbound TA sequence closer to the conformation of the unconstrained A-tract. It was reported earlier that, owing to their flexibility, TA steps can be accommodated in narrow minor grooves resembling an A-tract.28,29 The bending of the netropsin−DNA complexes predicted by our model (16 ± 1° for the A-tract and 18 ± 2° for the TA sequence, both to the minor groove; Table 1) agrees quantitatively with the experiment (16 and 19° to the minor groove, respectively).9,10 Thus, the model correctly describes bending of the A-tract and the alternating TA sequence induced by netropsin binding and predicts that netropsin shifts the TA oligomer toward the Atract conformation, in terms of not only bending but also in local structure (major groove, twist, roll, propeller). Because the other minor groove binders in the experiment are structurally similar to netropsin and induce similar bending, it is plausible to assume that they will induce a similar structural shift. This may have important functional implications. In many cases, it is the local structure that determines the unique biological properties of A-tracts.30 If the TA sequence is driven to mimic an A-tract structurally, it may also become functionally similar. Another application concerns binding of Py/Im polyamides to DNA. As a reference, we took the minor groove profile from the crystal of a polyamide−DNA complex reported by Chenoweth and Dervan (CD).4 To test our model, we investigated a DNA oligomer containing the 10-bp CD sequence in its center (Table 1). Imposing the minor groove profile yields DNA bending in quantitative agreement with the ligand-bound crystal data (crystal: 21°; model: 20 ± 1°, bending to the major groove in both cases; Table 1). The MD structures exhibit less variation and respect the palindromic symmetry of the naked sequence, whereas the naked and ligand-bound crystal structures are much more variable, probably due to packing forces (SI). This makes detailed structural comparison between MD and single-crystal data difficult. Analogous phenomena have been reported for other DNA crystals.20,27 Earlier tests have shown that modern MD simulations with the Amber ff99bsc0 force field reproduce the sequence-dependent B-DNA structure generally well.31−33 The force field deficiencies (e.g., slightly overestimated groove 3833



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sequences using pyrrole−imidazole polyamide microarrays. J. Am. Chem. Soc. 2013, 135, 3449−3457. (9) Tevis, D. S.; Kumar, A.; Stephens, C. E.; Boykin, D. W.; Wilson, W. D. Large, sequence-dependent effects on DNA conformation by minor groove binding compounds. Nucleic Acids Res. 2009, 37, 5550− 5558. (10) Hunt, R. A.; Munde, M.; Kumar, A.; Ismail, M. A.; Farahat, A. A.; Arafa, R. K.; Say, M.; Batista-Parra, A.; Tevis, D.; Boykin, D. W.; et al. Induced topological changes in DNA complexes: Influence of DNA sequences and small molecule structures. Nucleic Acids Res. 2011, 39, 4265−4274. (11) Lauria, A.; Montalbano, A.; Barraja, P.; Dattolo, G.; Almerico, A. M. DNA minor groove binders: An overview on molecular modeling and QSAR approaches. Curr. Med. Chem. 2007, 14, 2136−2160. (12) Rueda, M.; Luque, F. J.; Orozco, M. Nature of minor-groove binders−DNA complexes in the gas phase. J. Am. Chem. Soc. 2005, 127, 11690−11698. (13) Zacharias, M. Minor groove deformability of DNA: A molecular dynamics free energy simulation study. Biophys. J. 2006, 91, 882−891. (14) Vargiu, A. V.; Ruggerone, P.; Magistrato, A.; Carloni, P. Dissociation of minor groove binders from DNA: Insights from metadynamics simulations. Nucleic Acids Res. 2008, 36, 5910−5921. (15) Dolenc, J.; Gerster, S.; van Gunsteren, W. F. Molecular dynamics simulations shed light on the enthalpic and entropic driving forces that govern the sequence specific recognition between netropsin and DNA. J. Phys. Chem. B 2010, 114, 11164−11172. (16) Rohs, R.; Bloch, I.; Sklenar, H.; Shakked, Z. Molecular flexibility in ab initio drug docking to DNA: Binding-site and binding-mode transitions in all-atom Monte Carlo simulations. Nucleic Acids Res. 2005, 33, 7048−7057. (17) Landau, L. D.; Lifshitz, E. M. Statistical Physics, Part 1; Elsevier: Amsterdam, The Netherlands, 1980. (18) Perez, A.; Luque, F. J.; Orozco, M. Dynamics of B-DNA on the microsecond time scale. J. Am. Chem. Soc. 2007, 129, 14739−14745. (19) Perez, A.; Luque, F. J.; Orozco, M. Frontiers in molecular dynamics simulations of DNA. Acc. Chem. Res. 2012, 45, 196−205. (20) Drsata, T.; Perez, A.; Orozco, M.; Morozov, A. V.; Sponer, J.; Lankas, F. Structure, stiffness and substates of the Dickerson−Drew dodecamer. J. Chem. Theory Comput. 2013, 9, 707−721. (21) Wei, D.; Wilson, W. D.; Neidle, S. Small-molecule binding to the DNA minor groove is mediated by a conserved water cluster. J. Am. Chem. Soc. 2013, 135, 1369−1377. (22) Shatzky-Schwartz, M.; Arbuckle, N. D.; Eisenstein, M.; Rabinovich, D.; Bareket-Samish, A.; Haran, T. E.; Luisi, B. F.; Shakked, Z. X-ray and solution studies of DNA oligomers and implications for the structural basis of A-tract-dependent curvature. J. Mol. Biol. 1997, 267, 595−623. (23) Hizver, J.; Rozenberg, H.; Frolow, F.; Rabinovich, D.; Shakked, Z. DNA bending by an adenine-thymine tract and its role in gene regulation. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 8490−8495. (24) Rohs, R.; West, S. M.; Liu, P.; Honig, B. Nuance in the doublehelix and its role in protein−DNA recognition. Curr. Opin. Struct. Biol. 2009, 19, 171−177. (25) Perez, A.; Marchan, I.; Svozil, D.; Sponer, J.; Cheatham, T. E.; Laughton, C. A.; Orozco, M. Refinenement of the AMBER force field for nucleic acids: Improving the description of alpha/gamma conformers. Biophys. J. 2007, 92, 3817−3829. (26) Lu, X.-J.; Olson, W. K. 3DNA: A software package for the analysis, rebuilding and visualization of three-dimensional nucleic acid structures. Nucleic Acids Res. 2003, 31, 5108−5121. (27) Drsata, T.; Spackova, N.; Jurecka, P.; Zgarbova, M.; Sponer, J.; Lankas, F. Mechanical properties of symmetric and asymmetric DNA A-tracts: Implications for looping and nucleosome positioning. Nucleic Acids Res. 2014, 42, 7383−7394. (28) Rohs, R.; West, S. M.; Sosinsky, A.; Liu, P.; Mann, R. S.; Honig, B. The role of DNA shape in protein−DNA recognition. Nature 2009, 461, 1248−1253.

deformation energy whose parameters are inferred from unrestrained MD simulations of naked DNA, using the theory of thermodynamic fluctuations. We then assess the effect of minor groove binding of diamidines and Py/Im polyamides. The model yields changes of DNA bending in quantitative agreement with experiment and predicts potentially biologically relevant structural distortions in response to the minor groove binding. Our model can be readily applied to other problems such as allosteric effects of DNA overtwisting and adapted to study other molecular systems. Allostery is a general phenomenon, operative in a range of systems from microtubules to the ribosome,44,45 and we expect the present approach to find broad application.

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ASSOCIATED CONTENT

S Supporting Information *

Theory, supplementary discussion, datam including minor groove profiles, crystal structures, and structural profiles of the crystallographic and simulated structures, and references. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: fi[email protected]. Phone: +420 220 410 319. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Grant Agency of the Czech Republic (14-21893S to T.D. and F.L.), the Grant Agency of the Charles University (584213 to T.D.), the Academy of Sciences of the Czech Republic (RVO61388963 to T.D. and F.L.), and the European Regional Development Fund (CZ.1.05/2.1.00/03.0058 to M.Z. and P.J.). J.S. was supported by the project “CEITEC - Central European Institute of Technology” (CZ.1.05/1.1.00/02.0068) from European Regional Development Fund.

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REFERENCES

(1) Motlagh, H. N.; Wrabl, J. O.; Li, J.; Hilser, V. J. The ensemble nature of allostery. Nature 2014, 508, 331−339. (2) Chaires, J. B. Allostery: DNA does it, too. ACS Chem. Biol. 2008, 3, 207−209. (3) Moretti, R.; Donato, L. J.; Brezinski, M. L.; Stafford, R. L.; Hoff, H.; Thorson, J. S.; Dervan, P. B.; Ansari, A. Z. Targeted chemical wedges reveal the role of allosteric DNA modulation in protein−DNA assembly. ACS Chem. Biol. 2008, 3, 220−229. (4) Chenoweth, D. M.; Dervan, P. B. Allosteric modulation of DNA by small molecules. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 13175− 13179. (5) Kim, S.; Brostromer, E.; Xing, D.; Jin, J.; Chong, S.; Ge, H.; Wang, S.; Gu, C.; Yang, L.; Gao, Y. Q.; et al. Probing allostery through DNA. Science 2013, 339, 816−819. (6) Raskatov, J. A.; Nickols, N. G.; Hargrove, A. E.; Marinov, G. K.; Wold, B.; Dervan, P. B. Gene expression changes in a tumor xenograft by a pyrrole−imidazole polyamide. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 16041−16045. (7) Kang, J. S.; Meier, J. L.; Dervan, P. B. Design of sequence-specific DNA binding molecules for DNA methyltransferase inhibition. J. Am. Chem. Soc. 2014, 136, 3687−3694. (8) Singh, I.; Wendeln, C.; Clark, A. W.; Cooper, J. M.; Ravoo, B. J.; Burley, G. A. Sequence-selective detection of double-stranded DNA 3834



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(29) Watkins, S.; van Pouderoyen, G.; Sixma, T. K. Structural analysis of the bipartite DNA-binding domain of Tc3 transposase bound to transposon DNA. Nucleic Acids Res. 2004, 32, 4306−4312. (30) Haran, T. E.; Mohanty, U. The unique structure of A-tracts and intrinsic DNA bending. Q. Rev. Biophys. 2009, 42, 41−81. (31) Fujii, S.; Kono, H.; Takenaka, S.; Go, N.; Sarai, A. Sequencedependent DNA deformability studied using molecular dynamics simulations. Nucleic Acids Res. 2007, 35, 6063−6074. (32) Perez, A.; Lankas, F.; Luque, F. J.; Orozco, M. Towards a molecular dynamics consensus view of B-DNA flexibility. Nucleic Acids Res. 2008, 36, 2379−2394. (33) Dans, P. D.; Perez, A.; Faustino, I.; Lavery, R.; Orozco, M. Exploring polymorphisms in B-DNA helical conformations. Nucleic Acids Res. 2012, 40, 10668−10678. (34) Zhou, T.; Yang, L.; Yan, L.; Dror, I.; Machado, A. C. D.; Ghane, T.; Di Felice, R.; Rohs, R. DNAshape: A method for the highthroughput prediction of DNA structural features on a genomic scale. Nucleic Acids Res. 2013, 41, W56−W62. (35) Lankas, F.; Cheatham, T. E., III; Spackova, N.; Hobza, P.; Langowski, J.; Sponer, J. Critical effect of the N2 amino group on structure, dynamics and elasticity of polypurine tracts. Biophys. J. 2002, 82, 2592−2609. (36) Hancock, S. P.; Ghane, T.; Cascio, D.; Rohs, R.; Di Felice, R.; Johnson, R. C. Control of DNA minor groove width and Fis protein binding by the purine 2-amino group. Nucleic Acids Res. 2013, 41, 6750−6760. (37) Meyer, S.; Jost, D.; Theodorakopoulos, N.; Peyrard, M.; Lavery, R.; Everaers, R. Temperature dependence of the DNA double helix at the nanoscale: Structure, elasticity, and fluctuations. Biophys. J. 2013, 105, 1904−1914. (38) Olson, W. K.; Gorin, A. A.; Lu, X.-J.; Hock, L. M.; Zhurkin, V. B. DNA sequence-dependent deformability deduced from protein−DNA crystal complexes. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 11163−11168. (39) Lankas, F.; Sponer, J.; Langowski, J.; Cheatham, T. E., III. DNA basepair step deformability inferred from molecular dynamics simulations. Biophys. J. 2003, 85, 2872−2883. (40) Lankas, F.; Sponer, J.; Langowski, J.; Cheatham, T. E., III. DNA deformability at the base pair level. J. Am. Chem. Soc. 2004, 126, 4124− 4125. (41) Gonzalez, O.; Maddocks, J. H. Extracting parameters for basepair level models of DNA from molecular dynamics simulations. Theor. Chem. Acc. 2001, 106, 76−82. (42) Lankas, F.; Gonzalez, O.; Heffler, L. M.; Stoll, G.; Moakher, M.; Maddocks, J. H. On the parameterization of rigid base and basepair models of DNA from molecular dynamics simulations. Phys. Chem. Chem. Phys. 2009, 11, 10565−10588. (43) Gonzalez, O.; Petkeviciute, D.; Maddocks, J. H. A sequencedependent rigid-base model of DNA. J. Chem. Phys. 2013, 138, 055102. (44) Amos, L.; Lowe, J. The subtle allostery of microtubule dynamics. Nat. Struct. Mol. Biol. 2014, 21, 505−506. (45) Sothiselvam, S.; Liu, B.; Han, W.; Ramu, H.; Klepacki, D.; Atkinson, G. C.; Brauer, A.; Remm, M.; Tenson, T.; Schulten, K.; et al. Macrolide antibiotics allosterically predispose the ribosome for translation arrest. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 9804−9809.

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Mechanical Model of DNA Allostery - American Chemical Society

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