Free Energy Predictions of Ligand Binding to an α-Helix Using Steered Molecular Dynamics and Umbrella Sampling Simulations

2014 ◽  
Vol 54 (7) ◽  
pp. 2093-2104 ◽  
Author(s):  
Jan K. Marzinek ◽  
Peter J. Bond ◽  
Guoping Lian ◽  
Yanyan Zhao ◽  
Lujia Han ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ligand Binding ◽  
Steered Molecular Dynamics ◽  
Umbrella Sampling ◽  
Α Helix

The molecular mechanism of ligand unbinding from the human telomeric G-quadruplex by steered molecular dynamics and umbrella sampling simulations

2015 ◽  
Vol 17 (19) ◽  
pp. 12857-12869 ◽  
Author(s):  
Jia-Kai Zhou ◽  
Dah-Yen Yang ◽  
Sheh-Yi Sheu
Keyword(s):  
Mechanical Properties ◽  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Mechanism ◽  
Steered Molecular Dynamics ◽  
Umbrella Sampling ◽  
Energy Profiles ◽  
G Quadruplex ◽  
Free Energy Profiles

The mechanical properties and kinetic pathways of the ligand BMVC unbinding from the G-quadruplex were investigated via the computation of free energy profiles.

scholarly journals Comparison of Umbrella Sampling and Steered Molecular Dynamics Methods for Computing Free Energy Profiles of Toluene Molecules through Phospholipid Bilayers

2019 ◽  
Author(s):  
Sang Noh ◽  
Rebecca Notman
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Computational Efficiency ◽  
Steered Molecular Dynamics ◽  
Umbrella Sampling ◽  
Energy Profiles ◽  
Toluene Molecule ◽  
Molecular Dynamics Methods ◽  
Viable Approach ◽  
The Cost

In this study, we use Molecular Dynamics (MD) to analyze three different corrections of the Steered Molecular Dynamics (SMD) implementation of Jarzynski's Equality (JE) to calculate the FE change for the translocation of a toluene molecule across a lipid bilayer, and compare the accuracy and computational efficiency of these approaches to the results obtained using Umbrella Sampling (US). We show that when computing the free energy profile of a small molecule across a model membrane, the SMD approach suffers from sampling issues that may be alleviated through the use of a slower pulling velocity, but at the cost of computational efficiency. We deduce that, despite its drawbacks, US remains the more viable approach of the two for computing the free energy (FE) profile.

Comparison of Umbrella Sampling and Steered Molecular Dynamics Methods for Computing Free Energy Profiles of Aromatic Substrates through Phospholipid Bilayers

2020 ◽  
Author(s):  
Sang Noh ◽  
Rebecca Notman
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Lipid Bilayer ◽  
Lipid Membranes ◽  
Steered Molecular Dynamics ◽  
Umbrella Sampling ◽  
Reaction Coordinate ◽  
Aromatic Substrates ◽  
Show Evidence ◽  
Viable Approach

Understanding the permeation of molecules through lipid membranes is fundamental for predicting the cellular uptake of solutes and drug delivery mechanisms. In molecular simulations the usual approach is to compute the free energy (FE) profile of a molecule across a model lipid bilayer, which can then be used to estimate the permeability of the molecule. Umbrella sampling (US), which involves carrying out a series of biased simulations along a defined reaction coordinate (usually the bilayer normal direction), is a popular method for the computation of such FE profiles. However, US can be challenging to implement because the results are dependent on the strength of the biasing potential and the spacing of windows along the reaction coordinate, which, in practice, are usually optimized by an inefficient trial and error approach. The Steered Molecular Dynamics implementation of the Jarzynski Equality (JE-SMD) has been identified as an alternative to equilibrium sampling methods for measuring the FE change across a reaction coordinate. In the JE-SMD approach, equilibrium FE values are evaluated from the average of rapid non-equilibrium trajectories, thus avoiding the practical issues that come with US. Here, we use three different corrections of the JE-SMD method to calculate the FE change for the translocation of two aromatic substrates, phenylalanine and toluene, across a lipid bilayer, and compare the accuracy and computational efficiency of these approaches to the results obtained using US. We show evidence that when computing the free energy profile, the JE-SMD approach suffers from insufficient sampling convergence of the bilayer environment, and is dependent on the characteristic of the aromatic substrate itself. We deduce that, despite its drawbacks, US remains the more viable approach of the two for computing the FE profile.

scholarly journals Comparison of Umbrella Sampling and Steered Molecular Dynamics Methods for Computing Free Energy Profiles of Toluene Molecules through Phospholipid Bilayers

2019 ◽  
Author(s):  
Sang Noh ◽  
Rebecca Notman
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Computational Efficiency ◽  
Steered Molecular Dynamics ◽  
Umbrella Sampling ◽  
Energy Profiles ◽  
Toluene Molecule ◽  
Molecular Dynamics Methods ◽  
Viable Approach ◽  
The Cost

In this study, we use Molecular Dynamics (MD) to analyze three different corrections of the Steered Molecular Dynamics (SMD) implementation of Jarzynski's Equality (JE) to calculate the FE change for the translocation of a toluene molecule across a lipid bilayer, and compare the accuracy and computational efficiency of these approaches to the results obtained using Umbrella Sampling (US). We show that when computing the free energy profile of a small molecule across a model membrane, the SMD approach suffers from sampling issues that may be alleviated through the use of a slower pulling velocity, but at the cost of computational efficiency. We deduce that, despite its drawbacks, US remains the more viable approach of the two for computing the free energy (FE) profile.

Comparison of Umbrella Sampling and Steered Molecular Dynamics Methods for Computing Free Energy Profiles of Aromatic Substrates through Phospholipid Bilayers

2020 ◽  
Author(s):  
Sang Noh ◽  
Rebecca Notman
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Lipid Bilayer ◽  
Lipid Membranes ◽  
Steered Molecular Dynamics ◽  
Umbrella Sampling ◽  
Reaction Coordinate ◽  
Aromatic Substrates ◽  
Show Evidence ◽  
Viable Approach

Understanding the permeation of molecules through lipid membranes is fundamental for predicting the cellular uptake of solutes and drug delivery mechanisms. In molecular simulations the usual approach is to compute the free energy (FE) profile of a molecule across a model lipid bilayer, which can then be used to estimate the permeability of the molecule. Umbrella sampling (US), which involves carrying out a series of biased simulations along a defined reaction coordinate (usually the bilayer normal direction), is a popular method for the computation of such FE profiles. However, US can be challenging to implement because the results are dependent on the strength of the biasing potential and the spacing of windows along the reaction coordinate, which, in practice, are usually optimized by an inefficient trial and error approach. The Steered Molecular Dynamics implementation of the Jarzynski Equality (JE-SMD) has been identified as an alternative to equilibrium sampling methods for measuring the FE change across a reaction coordinate. In the JE-SMD approach, equilibrium FE values are evaluated from the average of rapid non-equilibrium trajectories, thus avoiding the practical issues that come with US. Here, we use three different corrections of the JE-SMD method to calculate the FE change for the translocation of two aromatic substrates, phenylalanine and toluene, across a lipid bilayer, and compare the accuracy and computational efficiency of these approaches to the results obtained using US. We show evidence that when computing the free energy profile, the JE-SMD approach suffers from insufficient sampling convergence of the bilayer environment, and is dependent on the characteristic of the aromatic substrate itself. We deduce that, despite its drawbacks, US remains the more viable approach of the two for computing the FE profile.

Displacement of carbonates in Ca2UO2(CO3)3 by amidoxime-based ligands from free-energy simulations

2018 ◽  
Vol 47 (5) ◽  
pp. 1604-1613 ◽  
Author(s):  
Bo Li ◽  
Chad Priest ◽  
De-en Jiang
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Umbrella Sampling ◽  
Nacl Solution ◽  
Classical Molecular Dynamics ◽  
Energy Profiles ◽  
Energy Simulations ◽  
Dynamics Simulations ◽  
Free Energy Profiles

Classical molecular dynamics simulations coupled with umbrella sampling reveal the atomistic processes and free-energy profiles of the displacement of carbonate groups in the Ca2UO2(CO3)3 complex by amidoxime-based ligands in a 0.5 M NaCl solution.

scholarly journals Constant velocity pulling and unfolding of thyroid hormone receptor by steered molecular dynamics

BIBECHANA ◽  
2020 ◽  
Vol 17 ◽  
pp. 50-57
Author(s):  
Tika Ram Lamichhane ◽  
Hari Prasad Lamichhane
Keyword(s):  
Molecular Dynamics ◽  
Thyroid Hormone ◽  
Ligand Binding ◽  
Hormone Receptor ◽  
Constant Velocity ◽  
Thyroid Hormone Receptor ◽  
Steered Molecular Dynamics ◽  
Electrostatic Energy ◽  
Gene Expressions ◽  
Globular Form

Unfolding pathways of T3 liganded thyroid hormone receptor (THRT3) can be studied by using the protocols of steered molecular dynamics (SMD). Theory of constant velocity pulling has been implemented to the structure of THRT3 in a neutral water-ion solution equilibrated up to 20 ns. The globular form of THRT3 is completely unfolded extending N-C termini from 38 Å to 876 Å at a constant speed of 0.1 Å/ps by means of 8.5 ns long SMD simulations. The peak force measured in the intermediate conformations is related to a burst of backbone H-bonds among a-helices and b-hairpins. With decrease in H-bonds, electrostatic energy increases by losing gradually the secondary structure and separating a and b-strands in solution. The force at the end (t > 8.5 ns) increases steeply with the large increase in bond-angle and bond-length potentials when the system becomes completely unfolded. The hydrophobic ligand binding domain (LBD) of THR-b with load bearing H-bonds protects T3 from water attack.  Even after complete unfolding of THR-b LBD, the position of T3 is not deviated more than 2.5 Å and a large number of water molecules remain in the surrounding of this domain area. This is a strong evidence for the mechanochemical stability of a receptor protein’s LBD towards hormone activated gene expressions followed by ligand binding and dissociation. BIBECHANA 17 (2020) 50-57

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