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  1. Article ; Online: Scaling regimes for wormlike chains confined to cylindrical surfaces under tension.

    Morrison, Greg / Thirumalai, D

    The European physical journal. E, Soft matter

    2024  Volume 47, Issue 1, Page(s) 6

    Abstract: We compute the free energy of confinement [Formula: see text] for a wormlike chain (WLC), with persistence length [Formula: see text], that is confined to the surface of a cylinder of radius R under an external tension f using a mean field variational ... ...

    Abstract We compute the free energy of confinement [Formula: see text] for a wormlike chain (WLC), with persistence length [Formula: see text], that is confined to the surface of a cylinder of radius R under an external tension f using a mean field variational approach. For long chains, we analytically determine the behavior of the chain in a variety of regimes, which are demarcated by the interplay of [Formula: see text], the Odijk deflection length ([Formula: see text]), and the Pincus length ([Formula: see text], with [Formula: see text] being the thermal energy). The theory accurately reproduces the Odijk scaling for strongly confined chains at [Formula: see text], with [Formula: see text]. For moderate values of f, the Odijk scaling is discernible only when [Formula: see text] for strongly confined chains. Confinement does not significantly alter the scaling of the mean extension for sufficiently high tension. The theory is used to estimate unwrapping forces for DNA from nucleosomes.
    Language English
    Publishing date 2024-01-22
    Publishing country France
    Document type Journal Article
    ZDB-ID 2004003-9
    ISSN 1292-895X ; 1292-8941
    ISSN (online) 1292-895X
    ISSN 1292-8941
    DOI 10.1140/epje/s10189-023-00384-6
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  2. Article ; Online: A maximum-entropy model to predict 3D structural ensembles of chromatin from pairwise distances with applications to interphase chromosomes and structural variants.

    Shi, Guang / Thirumalai, D

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 1150

    Abstract: The principles that govern the organization of genomes, which are needed for an understanding of how chromosomes are packaged and function in eukaryotic cells, could be deciphered if the three-dimensional (3D) structures are known. Recently, single-cell ... ...

    Abstract The principles that govern the organization of genomes, which are needed for an understanding of how chromosomes are packaged and function in eukaryotic cells, could be deciphered if the three-dimensional (3D) structures are known. Recently, single-cell imaging techniques have been developed to determine the 3D coordinates of genomic loci in vivo. Here, we introduce a computational method (Distance Matrix to Ensemble of Structures, DIMES), based on the maximum entropy principle, with experimental pairwise distances between loci as constraints, to generate a unique ensemble of 3D chromatin structures. Using the ensemble of structures, we quantitatively account for the distribution of pairwise distances, three-body co-localization, and higher-order interactions. The DIMES method can be applied to both small and chromosome-scale imaging data to quantify the extent of heterogeneity and fluctuations in the shapes across various length scales. We develop a perturbation method in conjunction with DIMES to predict the changes in 3D structures from structural variations. Our method also reveals quantitative differences between the 3D structures inferred from Hi-C and those measured in imaging experiments. Finally, the physical interpretation of the parameters extracted from DIMES provides insights into the origin of phase separation between euchromatin and heterochromatin domains.
    MeSH term(s) Chromatin/genetics ; Entropy ; Euchromatin ; Heterochromatin ; Interphase/genetics
    Chemical Substances Chromatin ; Euchromatin ; Heterochromatin
    Language English
    Publishing date 2023-03-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-36412-4
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  3. Article ; Online: Watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time.

    Hori, Naoto / Thirumalai, D

    Nucleic acids research

    2023  Volume 51, Issue 19, Page(s) 10737–10751

    Abstract: Folding of ribozymes into well-defined tertiary structures usually requires divalent cations. How Mg2+ ions direct the folding kinetics has been a long-standing unsolved problem because experiments cannot detect the positions and dynamics of ions. To ... ...

    Abstract Folding of ribozymes into well-defined tertiary structures usually requires divalent cations. How Mg2+ ions direct the folding kinetics has been a long-standing unsolved problem because experiments cannot detect the positions and dynamics of ions. To address this problem, we used molecular simulations to dissect the folding kinetics of the Azoarcus ribozyme by monitoring the path each molecule takes to reach the folded state. We quantitatively establish that Mg2+ binding to specific sites, coupled with counter-ion release of monovalent cations, stimulate the formation of secondary and tertiary structures, leading to diverse pathways that include direct rapid folding and trapping in misfolded structures. In some molecules, key tertiary structural elements form when Mg2+ ions bind to specific RNA sites at the earliest stages of the folding, leading to specific collapse and rapid folding. In others, the formation of non-native base pairs, whose rearrangement is needed to reach the folded state, is the rate-limiting step. Escape from energetic traps, driven by thermal fluctuations, occurs readily. In contrast, the transition to the native state from long-lived topologically trapped native-like metastable states is extremely slow. Specific collapse and formation of energetically or topologically frustrated states occur early in the assembly process.
    MeSH term(s) RNA, Catalytic/chemistry ; Nucleic Acid Conformation ; Magnesium ; RNA/chemistry ; Ions ; Kinetics
    Chemical Substances RNA, Catalytic ; Magnesium (I38ZP9992A) ; RNA (63231-63-0) ; Ions
    Language English
    Publishing date 2023-09-25
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkad755
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  4. Article ; Online: Allosteric communication between ACE2 active site and binding interface with SARS-CoV-2.

    Mugnai, Mauro L / Thirumalai, D

    The Journal of chemical physics

    2023  Volume 158, Issue 21

    Abstract: SARS-CoV-2, the virus causing COVID-19, initiates cell invasion by deploying a receptor binding domain (RBD) to recognize the host transmembrane peptidase angiotensin-converting enzyme 2 (ACE2). Numerous experimental and theoretical studies have adopted ... ...

    Abstract SARS-CoV-2, the virus causing COVID-19, initiates cell invasion by deploying a receptor binding domain (RBD) to recognize the host transmembrane peptidase angiotensin-converting enzyme 2 (ACE2). Numerous experimental and theoretical studies have adopted high-throughput and structure-guided approaches to (i) understand how the RBD recognizes ACE2, (ii) rationalize, and (iii) predict the effect of viral mutations on the binding affinity. Here, we investigate the allosteric signal triggered by the dissociation of the ACE2-RBD complex. To this end, we construct an Elastic Network Model (ENM), and we use the Structural Perturbation Method (SPM). Our key result is that complex dissociation opens the ACE2 substrate-binding cleft located away from the interface and that fluctuations of the ACE2 binding cleft are facilitated by RBD binding. These and other observations provide a structural and dynamical basis for the influence of SARS-CoV-2 on ACE2 enzymatic activity. In addition, we identify a conserved glycine (G502 in SARS-CoV-2) as a key participant in complex disassembly.
    MeSH term(s) Humans ; Angiotensin-Converting Enzyme 2/chemistry ; Binding Sites ; Catalytic Domain ; Mutation ; Protein Binding ; SARS-CoV-2
    Chemical Substances Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; ACE2 protein, human (EC 3.4.17.23)
    Language English
    Publishing date 2023-05-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3113-6
    ISSN 1089-7690 ; 0021-9606
    ISSN (online) 1089-7690
    ISSN 0021-9606
    DOI 10.1063/5.0137654
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    In stock of ZB MED Bonn / Germany

    Z 4' 49/16: Show issues

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  5. Article ; Online: Autobiography of Dave Thirumalai.

    Thirumalai, Dave

    The journal of physical chemistry. B

    2022  Volume 125, Issue 51, Page(s) 13834–13839

    Language English
    Publishing date 2022-01-21
    Publishing country United States
    Document type Journal Article
    ISSN 1520-5207
    ISSN (online) 1520-5207
    DOI 10.1021/acs.jpcb.1c10031
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  6. Article ; Online: Structural basis for the preservation of a subset of topologically associating domains in interphase chromosomes upon cohesin depletion.

    Jeong, Davin / Shi, Guang / Li, Xin / Thirumalai, D

    eLife

    2024  Volume 12

    Abstract: Compartment formation in interphase chromosomes is a result of spatial segregation between euchromatin and heterochromatin on a few megabase pairs (Mbp) scale. On the sub-Mbp scales, topologically associating domains (TADs) appear as interacting domains ... ...

    Abstract Compartment formation in interphase chromosomes is a result of spatial segregation between euchromatin and heterochromatin on a few megabase pairs (Mbp) scale. On the sub-Mbp scales, topologically associating domains (TADs) appear as interacting domains along the diagonal in the ensemble averaged Hi-C contact map. Hi-C experiments showed that most of the TADs vanish upon deleting cohesin, while the compartment structure is maintained, and perhaps even enhanced. However, closer inspection of the data reveals that a non-negligible fraction of TADs is preserved (P-TADs) after cohesin loss. Imaging experiments show that, at the single-cell level, TAD-like structures are present
    MeSH term(s) Animals ; Mice ; Humans ; Chromatin ; Cohesins ; Chromosomes ; Heterochromatin ; Interphase
    Chemical Substances Chromatin ; Cohesins ; Heterochromatin
    Language English
    Publishing date 2024-03-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.88564
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  7. Article ; Online: Brewing COFFEE: A Sequence-Specific Coarse-Grained Energy Function for Simulations of DNA-Protein Complexes.

    Chakraborty, Debayan / Mondal, Balaka / Thirumalai, D

    Journal of chemical theory and computation

    2024  Volume 20, Issue 3, Page(s) 1398–1413

    Abstract: DNA-protein interactions are pervasive in a number of biophysical processes ranging from transcription and gene expression to chromosome folding. To describe the structural and dynamic properties underlying these processes accurately, it is important to ... ...

    Abstract DNA-protein interactions are pervasive in a number of biophysical processes ranging from transcription and gene expression to chromosome folding. To describe the structural and dynamic properties underlying these processes accurately, it is important to create transferable computational models. Toward this end, we introduce
    MeSH term(s) Nucleosomes ; DNA/chemistry ; Thermodynamics
    Chemical Substances Nucleosomes ; DNA (9007-49-2)
    Language English
    Publishing date 2024-01-19
    Publishing country United States
    Document type Journal Article
    ISSN 1549-9626
    ISSN (online) 1549-9626
    DOI 10.1021/acs.jctc.3c00833
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  8. Article: Cooperativity and Folding Kinetics in a Multidomain Protein with Interwoven Chain Topology.

    Liu, Zhenxing / Thirumalai, D

    ACS central science

    2022  Volume 8, Issue 6, Page(s) 763–774

    Abstract: Although a large percentage of eukaryotic proteomes consist of proteins with multiple domains, not much is known about their assembly mechanism, especially those with intricate native state architectures. Some have a complex topology in which the ... ...

    Abstract Although a large percentage of eukaryotic proteomes consist of proteins with multiple domains, not much is known about their assembly mechanism, especially those with intricate native state architectures. Some have a complex topology in which the structural elements along the sequence are interwoven in such a manner that the domains cannot be separated by cutting at any location along the sequence. Such proteins are multiply connected multidomain proteins (MMPs) with the three-domain (NMP, LID, and CORE) phosphotransferase enzyme adenylate kinase (ADK) being an example. We devised a coarse-grained model to simulate ADK folding initiated by changing either the temperature or guanidinium chloride (GdmCl) concentration. The simulations reproduce the experimentally measured melting temperatures (associated with two equilibrium transitions), FRET efficiency as a function of GdmCl concentration, and the folding times quantitatively. Although the NMP domain orders independently, cooperative interactions between the LID and the CORE domains are required for complete assembly of the enzyme. Kinetic simulations show that, on the collapse time scale, multiple interconnected metastable states are populated, attesting to the folding heterogeneity. The network of kinetically connected states reveals that the CORE domain folds only after the NMP and LID domains, reflecting the interwoven nature of the chain topology.
    Language English
    Publishing date 2022-05-19
    Publishing country United States
    Document type Journal Article
    ISSN 2374-7943
    ISSN 2374-7943
    DOI 10.1021/acscentsci.2c00140
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  9. Article ; Online: A mathematical model for phenotypic heterogeneity in breast cancer with implications for therapeutic strategies.

    Li, Xin / Thirumalai, D

    Journal of the Royal Society, Interface

    2022  Volume 19, Issue 186, Page(s) 20210803

    Abstract: Inevitably, almost all cancer patients develop resistance to targeted therapy. Intratumour heterogeneity is a major cause of drug resistance. Mathematical models that explain experiments quantitatively are useful in understanding the origin of ... ...

    Abstract Inevitably, almost all cancer patients develop resistance to targeted therapy. Intratumour heterogeneity is a major cause of drug resistance. Mathematical models that explain experiments quantitatively are useful in understanding the origin of intratumour heterogeneity, which then could be used to explore scenarios for efficacious therapy. Here, we develop a mathematical model to investigate intratumour heterogeneity in breast cancer by exploiting the observation that HER2+ and HER2- cells could divide symmetrically or asymmetrically. Our predictions for the evolution of cell fractions are in quantitative agreement with single-cell experiments. Remarkably, the colony size of HER2+ cells emerging from a single HER2- cell (or vice versa), which occurs in about four cell doublings, also agrees with experimental results, without tweaking any parameter in the model. The theory explains experimental data on the responses of breast tumours under different treatment protocols. We then used the model to predict that, not only the order of two drugs, but also the treatment period for each drug and the tumour cell plasticity could be manipulated to improve the treatment efficacy. Mathematical models, when integrated with data on patients, make possible exploration of a broad range of parameters readily, which might provide insights in devising effective therapies.
    MeSH term(s) Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Drug Resistance, Neoplasm ; Female ; Humans ; Models, Theoretical
    Language English
    Publishing date 2022-01-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2156283-0
    ISSN 1742-5662 ; 1742-5689
    ISSN (online) 1742-5662
    ISSN 1742-5689
    DOI 10.1098/rsif.2021.0803
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  10. Article ; Online: Transcription-induced active forces suppress chromatin motion.

    Shin, Sucheol / Shi, Guang / Cho, Hyun Woo / Thirumalai, D

    Proceedings of the National Academy of Sciences of the United States of America

    2024  Volume 121, Issue 12, Page(s) e2307309121

    Abstract: The organization of interphase chromosomes in a number of species is starting to emerge thanks to advances in a variety of experimental techniques. However, much less is known about the dynamics, especially in the functional states of chromatin. Some ... ...

    Abstract The organization of interphase chromosomes in a number of species is starting to emerge thanks to advances in a variety of experimental techniques. However, much less is known about the dynamics, especially in the functional states of chromatin. Some experiments have shown that the motility of individual loci in human interphase chromosome decreases during transcription and increases upon inhibiting transcription. This is a counterintuitive finding because it is thought that the active mechanical force (
    MeSH term(s) Humans ; Chromatin/genetics ; Chromosomes, Human ; Transcription Factors/genetics ; Interphase/genetics ; RNA Polymerase II/genetics
    Chemical Substances Chromatin ; Transcription Factors ; RNA Polymerase II (EC 2.7.7.-)
    Language English
    Publishing date 2024-03-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2307309121
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
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