scholarly journals Probing the Relationship between Anti-Pneumocystis carinii Activity and DNA Binding of Bisamidines by Molecular Dynamics Simulations

Molecules ◽  
2015 ◽  
Vol 20 (4) ◽  
pp. 5942-5964 ◽  
Author(s):  
Teresa Żołek ◽  
Dorota Maciejewska ◽  
Jerzy Żabiński ◽  
Paweł Kaźmierczak ◽  
Mateusz Rezler
Keyword(s):  
Molecular Dynamics ◽  
Dna Binding ◽  
Molecular Dynamics Simulations ◽  
Pneumocystis Carinii ◽  
Dynamics Simulations ◽  
The Relationship

Unraveling cGAS catalytic mechanism upon DNA activation through molecular dynamics simulations

2021 ◽  
Author(s):  
Jordi Soler ◽  
Pedro Paiva ◽  
Maria Joao Joao Ramos ◽  
Pedro Alexandrino Fernandes ◽  
Marie Brut
Keyword(s):  
Molecular Dynamics ◽  
Dna Binding ◽  
Molecular Dynamics Simulations ◽  
Cyclic Gmp ◽  
Catalytic Mechanism ◽  
System P ◽  
Dynamics Simulations ◽  
Cyclic Dinucleotide

Cyclic GMP-AMP Synthase (cGAS) is activated upon DNA binding and catalyzes the synthesis of 2’,3’-cGAMP from GTP and ATP. This cyclic dinucleotide is a messenger that triggers the autoimmune system...

scholarly journals Somatic mutations in CTCF zinc fingers produce cellular phenotypes explained by structure-function relationships

2021 ◽  
Author(s):  
John EJ Rasko ◽  
Charles Geoffrey Bailey ◽  
Shailendra Gupta ◽  
Cynthia Metierre ◽  
Punkaja Amarasekera ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Cell Growth ◽  
Dna Binding ◽  
Structure Function ◽  
Molecular Dynamics Simulations ◽  
Zinc Fingers ◽  
Cancer Genome ◽  
Tumour Suppressor ◽  
Dynamics Simulations ◽  
Cellular Phenotypes

Background: Human cancers commonly contain mutations in transcription factors that lead to aberrant DNA binding or altered effector function at target sites. One such factor significantly mutated in cancer is the evolutionarily-conserved CCCTC-binding factor (CTCF), which has fundamental roles in maintaining chromatin architecture and transcriptional regulation. Numerous cancer genome sequencing and functional studies have revealed CTCF's role as a haploinsufficient tumour suppressor gene. However, to date, structure-function relationships of somatic CTCF mutations have not been examined. Methods: We collated somatic CTCF mutations from cancer genome portals and published studies to determine their nature, frequency, distribution and potential functional impact. We undertook an in-depth examination of 5 CTCF missense zinc finger (ZF) mutations occurring within key intra- and inter-ZF residues. We performed functional analyses including cell growth, colony-formation, chromatin immunoprecipitation and transcriptional reporter assays. Based on their homology, each ZF mutation was then modelled on CTCF's ZF domain crystal structure and its structural impact analysed using molecular dynamics simulations. Results: We observed an enrichment of somatic missense mutations occurring in the ZF region of CTCF, compared to the unstructured N- and C-termini. Functional characterisation of CTCF ZF mutations revealed a complete (L309P, R339W, R377H) or intermediate (R339Q) abrogation as well as an enhancement (G420D) of the anti-proliferative effects of CTCF. DNA binding at select sites was disrupted and transcriptional regulatory activities abrogated. In silico mutagenesis revealed that L309P had the highest mutation energy and thus most severe impact on protein stability. Molecular docking and molecular dynamics simulations confirmed that mutations in residues specifically contacting DNA bases or backbone exhibited loss of DNA binding (R339Q, R339W, R377H). Remarkably, R339Q and G420D were stabilised by the formation of new primary DNA bonds. All mutations exhibited some loss or gain of bonds at neighbouring residues, often in adjacent zinc fingers. Conclusions: Our data confirm the significant negative impact haploinsufficient CTCF ZF mutations have on its tumour suppressor function. A spectrum of loss-, change- and gain-of-function impacts in CTCF zinc fingers are observed in cell growth regulation and gene regulatory activities. We have established that diverse cellular phenotypes in CTCF are explained by examining structure-function relationships.

On the Relationship of the Relative Intensity I3 and a Cavity Number as Obtained from Computer Simulations

2012 ◽  
Vol 733 ◽  
pp. 183-189 ◽  
Author(s):  
Dušan Račko
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Free Volume ◽  
Computer Simulations ◽  
Relative Intensity ◽  
Complex Behavior ◽  
Volume Analysis ◽  
Dynamics Simulations ◽  
Relationship Of ◽  
The Relationship

In this contribution a generalized picture of the cavity number behavior is obtained by means of molecular dynamics simulations and consequent free volume analysis. The cavity number obtained for free volume cavities defined by different probe radii shows a complex behavior with the temperature. The number of cavities determined by small probes drops with the temperature. The number of cavities determined by large probes increases. This complex behavior of the cavity number can be discussed with the distinct behavior of the relative intensity, as observed in the experiment, and a support for the most basic of assumptions, that the cavity number relates to the relative intensity, is given.

scholarly journals New Insights into Quinine–DNA Binding Using Raman Spectroscopy and Molecular Dynamics Simulations

2018 ◽  
Vol 122 (43) ◽  
pp. 9840-9851 ◽  
Author(s):  
David Punihaole ◽  
Riley J. Workman ◽  
Shiv Upadhyay ◽  
Craig Van Bruggen ◽  
Andrew J. Schmitz ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Raman Spectroscopy ◽  
Dna Binding ◽  
Molecular Dynamics Simulations ◽  
Dynamics Simulations
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