Catalytic Magnesium as a Door Stop for DNA Sliding

Wang, Hao; Elber, Ron

doi:10.1021/acs.jpcb.1c00122

Cited by 3 publications

(3 citation statements)

References 28 publications

(49 reference statements)

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“…In typical chemical reactions, the transition state is associated with a significant free energy barrier and it spans only a small fraction of the reaction space . Here, the transition domain (a committor value of about 0.5, represented in teal in Figure ) is exceptionally broad and covers more than half of the relevant reaction space equivalent to the hydrophobic membrane interior.…”

Section: Resultsmentioning

confidence: 99%

Peptide Permeation across a Phosphocholine Membrane: An Atomically Detailed Mechanism Determined through Simulations and Supported by Experimentation

et al. 2022

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Cell-penetrating peptides (CPPs) facilitate translocation across biological membranes and are of significant biological and medical interest. Several CPPs can permeate into specific cells and organelles. We examine the incorporation and translocation of a novel anticancer CPP in a dioleoylphosphatidylcholine (DOPC) lipid bilayer membrane. The peptide, NAF-144–67, is a short fragment of a transmembrane protein, consisting of hydrophobic N-terminal and charged C-terminal segments. Experiments using fluorescently labeled NAF-144–67 in ∼100 nm DOPC vesicles and atomically detailed simulations conducted with Milestoning support a model in which a significant barrier for peptide-membrane entry is found at the interface between the aqueous solution and membrane. The initial step is the insertion of the N-terminal segment and the hydrophobic helix into the membrane, passing the hydrophilic head groups. Both experiments and simulations suggest that the free energy difference in the first step of the permeation mechanism in which the hydrophobic helix crosses the phospholipid head groups is −0.4 kcal mol–1 slightly favoring motion into the membrane. Milestoning calculations of the mean first passage time and the committor function underscore the existence of an early polar barrier followed by a diffusive barrierless motion in the lipid tail region. Permeation events are coupled to membrane fluctuations that are examined in detail. Our study opens the way to investigate in atomistic resolution the molecular mechanism, kinetics, and thermodynamics of CPP permeation to diverse membranes.

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Section: Resultsmentioning

confidence: 99%

Peptide Permeation across a Phosphocholine Membrane: An Atomically Detailed Mechanism Determined through Simulations and Supported by Experimentation

et al. 2022

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“…Analyzing the milestone-to-milestone transition statistics via a statistical framework, the kinetics and free-energy profile are estimated. This method has also been implemented in the software tool miles, ScMile and simulation enabled estimation of kinetic rates (SEEKR), and has been used to study a variety of complex biological problems including protein allosteric transitions, membrane permeation by small molecules, − protein small molecule interaction, ,− simple ligand–receptor binding, peptide transport through protein channels, , DNA protein interaction, protein conformational dynamics, etc. Apart from the necessity of having a predefined reaction coordinate, the milestones need to be placed far apart to preserve the assumption of Markovianity .…”

Section: Introductionmentioning

confidence: 99%

Markovian Weighted Ensemble Milestoning (M-WEM): Long-Time Kinetics from Short Trajectories

Ray

Stone

Andricioaei

2021

J. Chem. Theory Comput.

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We introduce a rare-event sampling scheme, named Markovian Weighted Ensemble Milestoning (M-WEM), which inlays a weighted ensemble framework within a Markovian milestoning theory to efficiently calculate thermodynamic and kinetic properties of long-time-scale biomolecular processes from short atomistic molecular dynamics simulations. M-WEM is tested on the Muller−Brown potential model, the conformational switching in alanine dipeptide, and the millisecond time-scale protein−ligand unbinding in a trypsin−benzamidine complex. Not only can M-WEM predict the kinetics of these processes with quantitative accuracy but it also allows for a scheme to reconstruct a multidimensional free-energy landscape along additional degrees of freedom, which are not part of the milestoning progress coordinate. For the ligand−receptor system, the experimental residence time, association and dissociation kinetics, and binding free energy could be reproduced using M-WEM within a simulation time of a few hundreds of nanoseconds, which is a fraction of the computational cost of other currently available methods, and close to 4 orders of magnitude less than the experimental residence time. Due to the high accuracy and low computational cost, the M-WEM approach can find potential applications in kinetics and free-energy-based computational drug design.

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“…Analyzing the milestone-to-milestone transition statistics via a mathematical framework, 37 the kinetics and free energy profile is estimated. This method has also been implemented in the software tools miles, 38 ScMile 39 and SEEKR, 40 and has been used to study a variety of complex biological problems including protein allosteric transitions, 41 membrane permeation by small molecules, 42–45 protein small molecule interaction, 40,46–48 simple ligand-receptor binding, 49 peptide transport through protein channels, 50,51 DNA protein interaction, 52 protein conformational dynamics 53 etc. Apart from the necessity of having a predefined reaction coordinate, the milestones need to be placed far apart to preserve the assumption of Markovianity.…”

Section: Introductionmentioning

confidence: 99%

Markovian Weighted Ensemble Milestoning (M-WEM): Long-time Kinetics from Short Trajectories

Andricioaei

2021

Preprint

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We introduce a rare-event sampling scheme, named Markovian Weighted Ensemble Milestoning (M-WEM), which inlays the weighted ensemble framework within a Markovian milestoning theory to efficiently calculate thermodynamic and kinetic properties of long-timescale biomolecular processes from short atomistic molecular dynamics simulations. We then showcase the application of this method to the Muller Brown potential model, the conformational switching in alanine dipeptide, and the millisecond timescale protein-ligand unbinding in the trypsin-benzamidine complex. Not only can we predict the kinetics of these processes with quantitative accuracy, but we also present a scheme to reconstruct a multidimensional free energy landscape, along additional degrees of freedom which are not part of the milestoning progress coordinate. For the ligand-receptor system, the experimental residence time, association and dissociation kinetics, and binding free energy could be reproduced using M-WEM approach within a few hundreds of nanoseconds simulation time, which is a fraction of the computational cost of other currently available methods, and close to four orders of magnitude less than the experimental residence time. Due to the high accuracy and low computational cost the M-WEM approach can find potential application in kinetics and free energy based computational drug design.

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Catalytic Magnesium as a Door Stop for DNA Sliding

Cited by 3 publications

References 28 publications

Peptide Permeation across a Phosphocholine Membrane: An Atomically Detailed Mechanism Determined through Simulations and Supported by Experimentation

Peptide Permeation across a Phosphocholine Membrane: An Atomically Detailed Mechanism Determined through Simulations and Supported by Experimentation

Markovian Weighted Ensemble Milestoning (M-WEM): Long-Time Kinetics from Short Trajectories

Markovian Weighted Ensemble Milestoning (M-WEM): Long-time Kinetics from Short Trajectories

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