scholarly journals Mesoscopic Model and Free Energy Landscape for Protein-DNA Binding Sites: Analysis of Cyanobacterial Promoters

2014 ◽  
Vol 10 (10) ◽  
pp. e1003835 ◽  
Author(s):  
Rafael Tapia-Rojo ◽  
Juan José Mazo ◽  
José Ángel Hernández ◽  
María Luisa Peleato ◽  
María F. Fillat ◽  
...  
Keyword(s):  
Free Energy ◽  
Dna Binding ◽  
Binding Sites ◽  
Energy Landscape ◽  
Free Energy Landscape ◽  
Mesoscopic Model ◽  
Dna Binding Sites

Free Energy Landscape Analysis of Mesoscopic Model for Finding DNA-Protein Binding Sites

2014 ◽  
pp. 81-85
Author(s):  
Rafael Tapia-Rojo ◽  
Juan José Mazo ◽  
Andrés González ◽  
M. Luisa Peleato ◽  
Maria F. Fillat ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Binding ◽  
Binding Sites ◽  
Energy Landscape ◽  
Landscape Analysis ◽  
Free Energy Landscape ◽  
Protein Binding Sites ◽  
Mesoscopic Model

scholarly journals Cation-induced kinetic heterogeneity of the intron–exon recognition in single group II introns

2015 ◽  
Vol 112 (11) ◽  
pp. 3403-3408 ◽  
Author(s):  
Danny Kowerko ◽  
Sebastian L. B. König ◽  
Miriam Skilandat ◽  
Daniela Kruschel ◽  
Mélodie C. A. S. Hadzic ◽  
...  
Keyword(s):  
Free Energy ◽  
Single Molecule ◽  
Binding Sites ◽  
Tertiary Structure ◽  
Energy Landscape ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Free Energy Landscape ◽  
Rna Tertiary Structure ◽  
Kinetic Heterogeneity

RNA is commonly believed to undergo a number of sequential folding steps before reaching its functional fold, i.e., the global minimum in the free energy landscape. However, there is accumulating evidence that several functional conformations are often in coexistence, corresponding to multiple (local) minima in the folding landscape. Here we use the 5′-exon–intron recognition duplex of a self-splicing ribozyme as a model system to study the influence of Mg2+ and Ca2+ on RNA tertiary structure formation. Bulk and single-molecule spectroscopy reveal that near-physiological M2+ concentrations strongly promote interstrand association. Moreover, the presence of M2+ leads to pronounced kinetic heterogeneity, suggesting the coexistence of multiple docked and undocked RNA conformations. Heterogeneity is found to decrease at saturating M2+ concentrations. Using NMR, we locate specific Mg2+ binding pockets and quantify their affinity toward Mg2+. Mg2+ pulse experiments show that M2+ exchange occurs on the timescale of seconds. This unprecedented combination of NMR and single-molecule Förster resonance energy transfer demonstrates for the first time to our knowledge that a rugged free energy landscape coincides with incomplete occupation of specific M2+ binding sites at near-physiological M2+ concentrations. Unconventional kinetics in nucleic acid folding frequently encountered in single-molecule experiments are therefore likely to originate from a spectrum of conformations that differ in the occupation of M2+ binding sites.

scholarly journals Dissociation pathways of the p53 DNA binding domain from DNA and critical roles of key residues elucidated by dPaCS-MD/MSM

2021 ◽  
Author(s):  
Mohamed Sobeh ◽  
Akio kitao
Keyword(s):  
Free Energy ◽  
Dna Binding ◽  
Energy Landscape ◽  
Minor Groove ◽  
Binding Domain ◽  
Free Energy Landscape ◽  
Dna Binding Domain ◽  
Major Groove ◽  
Dna Duplex ◽  
Key Residues

The dissociation process of the DNA binding domain of p53 (p53-DBD) from a DNA duplex that contains the consensus sequence, which is the specific target of p53-DBD, was investigated by a combination of dissociation parallel cascade selection molecular dynamics (dPaCS-MD) and the Markov state model (MSM). Based on an all-atom model including explicit solvent, we first simulated the p53-DBD dissociation processes by 75 trials of dPaCS-MD, which required an average simulation time of 11.2 ± 2.2 ns per trial. By setting the axis of the DNA duplex as the Z-axis and the binding side of p53-DBD on DNA as the + side of the X-axis, we found that dissociations took place along the +X and −Y directions (−Y directions) in 93% of the cases, while 7% of the cases moved along +X and +Y directions (+Y directions). Toward the −Y directions, p53-DBD dissociated first from the major groove and then detached from the minor groove, while unbinding from the minor groove occurred first in dissociations along the +Y directions. Analysis of the free energy landscape by MSM showed that loss of the minor groove interaction with p53-DBD toward the +Y directions incurred a relatively high energy cost (1.1 kcal/mol) upon a critical transition, whereas major groove detachment more frequently occurred with lower free energy costs. The standard binding free energy calculated from the free energy landscape was −10.9 ± 0.4 kcal/mol, which agrees with an experimental value of –11.1 kcal/mol. These results indicate that the dPaCS-MD/MSM combination can be a powerful tool to investigate dissociation mechanisms of two large molecules. Minor groove binding is mainly stabilized by R248, identified as the most important residue that tightly binds deep inside the minor groove. Analysis of the p53 key residues for DNA binding indicates high correlations with cancer-related mutations, confirming that impairment of the interactions between p53-DBD and DNA can be frequently related to cancer.

Determination of Base Flipping Free Energy Landscapes from Nonequilibrium Stratification

2019 ◽  
Author(s):  
Xiaohui Wang ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Sampling Technique ◽  
Umbrella Sampling ◽  
Energy Simulation ◽  
Nonlinear Dependence ◽  
Free Energy Landscape ◽  
Convergence Criterion ◽  
Base Flipping ◽  
Convergence Behavior

<p>Correct calculation of the variation of free energy upon base flipping is crucial in understanding the dynamics of DNA systems. The free energy landscape along the flipping pathway gives the thermodynamic stability and the flexibility of base-paired states. Although numerous free energy simulations are performed in the base flipping cases, no theoretically rigorous nonequilibrium techniques are devised and employed to investigate the thermodynamics of base flipping. In the current work, we report a general nonequilibrium stratification scheme for efficient calculation of the free energy landscape of base flipping in DNA duplex. We carefully monitor the convergence behavior of the equilibrium sampling based free energy simulation and the nonequilibrium stratification and determine the empirical length of time blocks required for converged sampling. Comparison between the performances of equilibrium umbrella sampling and nonequilibrium stratification is given. The results show that nonequilibrium free energy simulation is able to give similar accuracy and efficiency compared with the equilibrium enhanced sampling technique in the base flipping cases. We further test a convergence criterion we previously proposed and it comes out that the convergence behavior determined by this criterion agrees with those given by the time-invariant behavior of PMF and the nonlinear dependence of standard deviation on the sample size. </p>

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