Our genome represents Gigabytes of information that rest on a physical material known as chromatin. Throughout the lifetime of the cell, this information is copied, corrected, and modified by complex molecular assemblies that have evolved to interact with the chromatin via highly intricate mechanisms. In the context of all this activity, the fundamental task of the chromatin is to protect the delicate DNA polymer. The regulatory hub for these duties is a disc-shaped nucleoprotein known as the nucleosome, the smallest repeating architectural unit of chromatin.
The nucleosome is composed of approximately 150 base pairs of nucleic acid that are wrapped around four pairs of highly conserved proteins known as histones. Covalent modifications in the histones and the surrounding nucleic acid alter also the physical properties of the nucleosomes, which in turn, influence their interactions with chromatin factors. Some nucleosomes become more flexible such that their DNA is loose whereas others become more rigid such that their DNA is less accessible. Some other nucleosomes are decorated with electrostatic charges and novel functional groups that invite the assembly and action of transcription factors, chromatin remodelers, and modifier enzymes.
This diversity of nucleosomes introduces an additional layer of genetic information, i.e., the epigenetic code, and the exploitation of biophysical processes in the expression and inheritance of the epigenetic code invites a quantitative approach for their study.
The goal in our group is to elucidate the biophysical processes that influence the regulation of gene expression and inheritance at the molecular level. We employ tools of molecular modeling, atomistic simulations, and accelerated sampling to study how structural modifications in chromatin translate into differences in dynamics. These differences are often associated with distinct functions and purposes according to experimental input and validation. This association sets a basis for our simulations to provide a molecular picture of the underlying mechanisms.
One example of the crosstalk between epigenetics and physical factors occurs is illustrated here in the figure. From left to right: 1-nucleosome containing the canonical H3 histone (dark blue) has closed DNA ends. 2-nucleosome containing the centromere-specific H3 variant known as CENP-A (ice blue) exhibits asymmetrically open DNA ends as shown in the study involving Kale Lab (Boopathi et al., Nucl Acids Res, 2020). 3-CENP-A nucleosome bound to anti-chromatin antibodies (magenta) exhibits closed DNA ends just like its canonical counterpart. Kale Lab demonstrated and characterized this behavior computationally (Doğan et al., J Mol Biol, 2021). 4-Epigenetic modifications in DNA can lead to open DNA ends on both sides of the CENP-A nucleosome.
Zhou BR, Feng H, Kale S, Fox T, Khant H, de Val N, Ghirlando R, Panchenko AR, Bai Y. Distinct Structures and Dynamics of Chromatosomes with Different Human Linker Histone Isoforms.. Molecular cell. 2021 January ; 81 (1) : 166-182.e6. doi:10.1016/j.molcel.2020.10.038. Download
Deniz Doğan; Merve Arslan; Tuğçe Uluçay; Sibel Kalyoncu; Stefan Dimitrov; Seyit Kale. CENP-A nucleosome is a sensitive allosteric scaffold for DNA and chromatin factors. Journal of Molecular Biology. 2021 March ; 433 (6) . doi:10.1016/j.jmb.2020.166789. Download
Fanfan Hao, Seyit Kale, Stefan Dimitrov, Jeffrey J Hayes. Unraveling linker histone interactions in nucleosomes. Current Opinion in Structural Biology. 2021 December ; 71 : 87-93. doi:10.1016/j.sbi.2021.06.001. Download
Boopathi R, Danev R, Khoshouei M, Kale S, Nahata S, Ramos L, Angelov D, Dimitrov S, Hamiche A, Petosa C, Bednar J. Phase-plate cryo-EM structure of the Widom 601 CENP-A nucleosome core particle reveals differential flexibility of the DNA ends.. Nucleic acids research. 2020 June ; 48 (10) : 5735-5748. doi:10.1093/nar/gkaa246. Download
Kale S, Strickland M, Peterkofsky A, Liu J, Tjandra N. Model of a Kinetically Driven Crosstalk between Paralogous Protein Encounter Complexes.. Biophysical journal. 2019 November ; 117 (9) : 1655-1665. doi:10.1016/j.bpj.2019.09.035. Download
Strickland M, Kale S, Strub MP, Schwieters CD, Liu J, Peterkofsky A, Tjandra N. Potential Regulatory Role of Competitive Encounter Complexes in Paralogous Phosphotransferase Systems.. Journal of molecular biology. 2019 May ; 431 (12) : 2331-2342. doi:10.1016/j.jmb.2019.04.040. Download
Kale S, Goncearenco A, Markov Y, Landsman D, Panchenko AR. Molecular recognition of nucleosomes by binding partners.. Current Opinion in Structural Biology. 2019 June ; 56 : 164-170. doi:10.1016/j.sbi.2019.03.010. Download
Hada A, Hota SK, Luo J, Lin YC, Kale S, Shaytan AK, Bhardwaj SK, Persinger J, Ranish J, Panchenko AR, Bartholomew B. Histone Octamer Structure Is Altered Early in ISW2 ATP-Dependent Nucleosome Remodeling.. Cell Reports. 2019 July ; 28 (1) : 282-294.e6. doi:10.1016/j.celrep.2019.05.106. Download
Bai C, Kale S, Herzfeld J. Chemistry with semi-classical electrons: reaction trajectories auto-generated by sub-atomistic force fields.. Chemical science. 2017 June ; 8 (6) : 4203-4210. doi:10.1039/c7sc01181d. Download
Chen Y, Kale S, Weare J, Dinner AR, Roux B. Multiple Time-Step Dual-Hamiltonian Hybrid Molecular Dynamics - Monte Carlo Canonical Propagation Algorithm.. Journal of chemical theory and computation. 2016 April ; 12 (4) : 1449-1458. doi:10.1021/acs.jctc.5b00706. Download
Ekesan S, Kale S, Herzfeld J. Transferable pseudoclassical electrons for aufbau of atomic ions.. Journal of computational chemistry. 2014 June ; 35 (15) : 1159-64. doi:10.1002/jcc.23612. Download
Kale S, Sode O, Weare J, Dinner AR. Finding Chemical Reaction Paths with a Multilevel Preconditioning Protocol.. Journal of chemical theory and computation. 2014 December ; 10 (12) : 5467-5475. doi:10.1021/ct500852y. Download
Kale S, Herzfeld J. Natural polarizability and flexibility via explicit valency: the case of water.. The Journal of chemical physics. 2012 February ; 136 (8) : 084109. doi:10.1063/1.3688228. Download
Kale S, Herzfeld J. Proton defect solvation and dynamics in aqueous acid and base.. Angewandte Chemie (International ed. in English). 2012 October ; 51 (44) : 11029-32. doi:10.1002/anie.201203568. Download
Kale S, Herzfeld J, Dai S, Blank M. Lewis-inspired representation of dissociable water in clusters and Grotthuss chains.. Journal of biological physics. 2012 January ; 38 (1) : 49-59. doi:10.1007/s10867-011-9229-5. Download
Kale S, Herzfeld J. Pairwise long-range compensation for strongly ionic systems.. Journal of chemical theory and computation. 2011 November ; 7 (11) : 3620-3624. doi:10.1021/ct200392u. Download
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