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      The static and dynamic structural heterogeneities of B-DNA: extending Calladine–Dickerson rules

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          Abstract

          We present a multi-laboratory effort to describe the structural and dynamical properties of duplex B-DNA under physiological conditions. By processing a large amount of atomistic molecular dynamics simulations, we determine the sequence-dependent structural properties of DNA as expressed in the equilibrium distribution of its stochastic dynamics. Our analysis includes a study of first and second moments of the equilibrium distribution, which can be accurately captured by a harmonic model, but with nonlocal sequence-dependence. We characterize the sequence-dependent choreography of backbone and base movements modulating the non-Gaussian or anharmonic effects manifested in the higher moments of the dynamics of the duplex when sampling the equilibrium distribution. Contrary to prior assumptions, such anharmonic deformations are not rare in DNA and can play a significant role in determining DNA conformation within complexes. Polymorphisms in helical geometries are particularly prevalent for certain tetranucleotide sequence contexts and are always coupled to a complex network of coordinated changes in the backbone. The analysis of our simulations, which contain instances of all tetranucleotide sequences, allow us to extend Calladine–Dickerson rules used for decades to interpret the average geometry of DNA, leading to a set of rules with quantitative predictive power that encompass nonlocal sequence-dependence and anharmonic fluctuations.

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            Origins of specificity in protein-DNA recognition.

            Specific interactions between proteins and DNA are fundamental to many biological processes. In this review, we provide a revised view of protein-DNA interactions that emphasizes the importance of the three-dimensional structures of both macromolecules. We divide protein-DNA interactions into two categories: those when the protein recognizes the unique chemical signatures of the DNA bases (base readout) and those when the protein recognizes a sequence-dependent DNA shape (shape readout). We further divide base readout into those interactions that occur in the major groove from those that occur in the minor groove. Analogously, the readout of the DNA shape is subdivided into global shape recognition (for example, when the DNA helix exhibits an overall bend) and local shape recognition (for example, when a base pair step is kinked or a region of the minor groove is narrow). Based on the >1500 structures of protein-DNA complexes now available in the Protein Data Bank, we argue that individual DNA-binding proteins combine multiple readout mechanisms to achieve DNA-binding specificity. Specificity that distinguishes between families frequently involves base readout in the major groove, whereas shape readout is often exploited for higher resolution specificity, to distinguish between members within the same DNA-binding protein family.
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              Conformational analysis of nucleic acids revisited: Curves+

              We describe Curves+, a new nucleic acid conformational analysis program which is applicable to a wide range of nucleic acid structures, including those with up to four strands and with either canonical or modified bases and backbones. The program is algorithmically simpler and computationally much faster than the earlier Curves approach, although it still provides both helical and backbone parameters, including a curvilinear axis and parameters relating the position of the bases to this axis. It additionally provides a full analysis of groove widths and depths. Curves+ can also be used to analyse molecular dynamics trajectories. With the help of the accompanying program Canal, it is possible to produce a variety of graphical output including parameter variations along a given structure and time series or histograms of parameter variations during dynamics.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                02 December 2019
                18 October 2019
                18 October 2019
                : 47
                : 21
                : 11090-11102
                Affiliations
                [1 ] Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology . Baldiri Reixac 10–12, 08028 Barcelona, Spain
                [2 ] Department of Biological Sciences, University of the Republic (UdelaR) , CENUR Gral. Rivera 1350, 50000 Salto, Uruguay
                [3 ] LBPA, École normale supérieure Paris-Saclay , 61 Av. du Pdt Wilson, Cachan 94235, France
                [4 ] Bases Moléculaires et Structurales des Systèmes Infectieux, Univ. Lyon I/CNRS UMR 5086, IBCP , 7 Passage du Vercors, Lyon 69367, France
                [5 ] Institute of Mathematics, Swiss Federal Institute of Technology (EPFL) , CH-1015 Lausanne, Switzerland
                [6 ] Faculty of Mathematics and Natural Sciences, Kaunas University of Technology , Studentų g. 50, 51368 Kaunas, Lithuania
                [7 ] Department of Biochemistry and Molecular Biology. University of Barcelona , 08028 Barcelona, Spain
                Author notes
                To whom correspondence should be addressed. Tel: +34 934039073; Email: pablo.dans@ 123456unorte.edu.uy
                Correspondence may also be addressed to John H. Maddocks. Tel: +41 216932762; Email: john.maddocks@ 123456epfl.ch
                Correspondence may also be addressed to Modesto Orozco. Tel: +34 934037155; Email: modesto.orozco@ 123456irbbarcelona.org

                The authors wish it to be known that, in their opinion, these co-authors should be regarded as Joint Second Authors.

                Author information
                http://orcid.org/0000-0002-5927-372X
                http://orcid.org/0000-0003-0939-618X
                Article
                gkz905
                10.1093/nar/gkz905
                6868377
                31624840
                b96a1422-09bc-4d1d-814e-a1a7a27a2cfb
                © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 06 October 2019
                : 25 September 2019
                : 18 May 2019
                Page count
                Pages: 13
                Funding
                Funded by: Spanish Ministry of Science
                Award ID: BFU2014-61670-EXP
                Award ID: BFU2014-52864-R
                Funded by: Catalan SGR
                Funded by: Instituto Nacional de Bioinformática
                Funded by: European Research Council 10.13039/501100000781
                Funded by: Horizon 2020 10.13039/100010661
                Award ID: 676556
                Funded by: Biomolecular & Bioinformatics Resources Platform
                Award ID: ISCIII PT 13/0001/0030
                Funded by: Fondo Europeo de Desarrollo Regional 10.13039/501100008530
                Funded by: MINECO 10.13039/501100003329
                Funded by: CNRS 10.13039/501100004794
                Funded by: ANR 10.13039/501100001665
                Award ID: ANR-12-BSV5-0017-01
                Funded by: Swiss National Science Foundation 10.13039/501100001711
                Award ID: 200020_163324
                Categories
                Computational Biology

                Genetics
                Genetics

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