scholarly journals Quantifying the Strength of a Salt Bridge by Neutron Scattering and Molecular Dynamics

2019 ◽  
Author(s):  
Philip E. Mason ◽  
Pavel Jungwirth ◽  
Elise Duboué-Dijon
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Neutron Scattering ◽  
Salt Bridge ◽  
Ion Pairing ◽  
Structural Features ◽  
Quantitative Agreement ◽  
Salt Bridges ◽  
Hydrophobic Contact ◽  
Guanidinium Cation

The molecular structure and strength of a model salt bridge between a guanidinium cation as the charged side chain group of arginine and the carboxylic group of acetate in an aqueous solutions is characterized by a combination of neutron diffraction with isotopic substitution and molecular dynamics simulations. Being able to recover the second order difference signal, the present neutron scattering experiments provide direct information about ion pairing in the investigated solution. At the same time, these measurements serve as benchmarks for assessing the quality of the force field employed in the simulation. We show that a standard non-polarizable force field, which tends to overestimate the strength of salt bridges, does not reproduce the structural features from neutron scattering pertinent to ion pairing. In contrast, a quantitative agreement with experiment is obtained when electronic polarization effects are accounted for in a mean-field way via charge scaling. Such simulations are then used to quantify the weak character of a fully hydrated salt bridge. Finally, on top of the canonical hydrogen-bonding binding mode between guanidinium and acetate, these simulations also point to another interaction motif involving an out-of-plane hydrophobic contact of the methyl group of acetate with the guanidinium cation.

scholarly journals Quantifying the Strength of a Salt Bridge by Neutron Scattering and Molecular Dynamics

2019 ◽  
Author(s):  
Philip E. Mason ◽  
Pavel Jungwirth ◽  
Elise Duboué-Dijon
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Neutron Scattering ◽  
Salt Bridge ◽  
Ion Pairing ◽  
Structural Features ◽  
Quantitative Agreement ◽  
Salt Bridges ◽  
Hydrophobic Contact ◽  
Guanidinium Cation

The molecular structure and strength of a model salt bridge between a guanidinium cation as the charged side chain group of arginine and the carboxylic group of acetate in an aqueous solutions is characterized by a combination of neutron diffraction with isotopic substitution and molecular dynamics simulations. Being able to recover the second order difference signal, the present neutron scattering experiments provide direct information about ion pairing in the investigated solution. At the same time, these measurements serve as benchmarks for assessing the quality of the force field employed in the simulation. We show that a standard non-polarizable force field, which tends to overestimate the strength of salt bridges, does not reproduce the structural features from neutron scattering pertinent to ion pairing. In contrast, a quantitative agreement with experiment is obtained when electronic polarization effects are accounted for in a mean-field way via charge scaling. Such simulations are then used to quantify the weak character of a fully hydrated salt bridge. Finally, on top of the canonical hydrogen-bonding binding mode between guanidinium and acetate, these simulations also point to another interaction motif involving an out-of-plane hydrophobic contact of the methyl group of acetate with the guanidinium cation.

scholarly journals Quantifying the Strength of a Salt Bridge by Neutron Scattering and Molecular Dynamics

2019 ◽  
Author(s):  
Philip E. Mason ◽  
Pavel Jungwirth ◽  
Elise Duboué-Dijon
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Neutron Scattering ◽  
Salt Bridge ◽  
Ion Pairing ◽  
Structural Features ◽  
Quantitative Agreement ◽  
Salt Bridges ◽  
Hydrophobic Contact ◽  
Guanidinium Cation

The molecular structure and strength of a model salt bridge between a guanidinium cation as the charged side chain group of arginine and the carboxylic group of acetate in an aqueous solutions is characterized by a combination of neutron diffraction with isotopic substitution and molecular dynamics simulations. Being able to recover the second order difference signal, the present neutron scattering experiments provide direct information about ion pairing in the investigated solution. At the same time, these measurements serve as benchmarks for assessing the quality of the force field employed in the simulation. We show that a standard non-polarizable force field, which tends to overestimate the strength of salt bridges, does not reproduce the structural features from neutron scattering pertinent to ion pairing. In contrast, a quantitative agreement with experiment is obtained when electronic polarization effects are accounted for in a mean-field way via charge scaling. Such simulations are then used to quantify the weak character of a fully hydrated salt bridge. Finally, on top of the canonical hydrogen-bonding binding mode between guanidinium and acetate, these simulations also point to another interaction motif involving an out-of-plane hydrophobic contact of the methyl group of acetate with the guanidinium cation.

scholarly journals How well do force fields capture the strength of salt bridges in proteins?

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4967 ◽  
Author(s):  
Mustapha Carab Ahmed ◽  
Elena Papaleo ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Force Fields ◽  
Salt Bridge ◽  
Dynamics Simulation ◽  
Ionic Interactions ◽  
Salt Bridges ◽  
Important Interaction ◽  
The Stability ◽  
Dynamics Simulations

Salt bridges form between pairs of ionisable residues in close proximity and are important interactions in proteins. While salt bridges are known to be important both for protein stability, recognition and regulation, we still do not have fully accurate predictive models to assess the energetic contributions of salt bridges. Molecular dynamics simulation is one technique that may be used study the complex relationship between structure, solvation and energetics of salt bridges, but the accuracy of such simulations depends on the force field used. We have used NMR data on the B1 domain of protein G (GB1) to benchmark molecular dynamics simulations. Using enhanced sampling simulations, we calculated the free energy of forming a salt bridge for three possible lysine-carboxylate ionic interactions in GB1. The NMR experiments showed that these interactions are either not formed, or only very weakly formed, in solution. In contrast, we show that the stability of the salt bridges is overestimated, to different extents, in simulations of GB1 using seven out of eight commonly used combinations of fixed charge force fields and water models. We also find that the Amber ff15ipq force field gives rise to weaker salt bridges in good agreement with the NMR experiments. We conclude that many force fields appear to overstabilize these ionic interactions, and that further work may be needed to refine our ability to model quantitatively the stability of salt bridges through simulations. We also suggest that comparisons between NMR experiments and simulations will play a crucial role in furthering our understanding of this important interaction.

Ion Pairing and Dielectric Decrement in Glycosaminoglycan Brushes

2020 ◽  
Author(s):  
James Sterling ◽  
Wenjuan Jiang ◽  
Wesley M. Botello-Smith ◽  
Yun L. Luo
Keyword(s):  
Molecular Dynamics ◽  
Ion Pairs ◽  
Mean Field ◽  
Salt Bridge ◽  
Ion Pairing ◽  
Donnan Potential ◽  
Mean Field Models ◽  
Ion Exclusion ◽  
Dynamics Simulations ◽  
Contact Ion Pairs

Molecular dynamics simulations of hyaluronic acid and heparin brushes are presented that show important effects of ion-pairing, water dielectric decrease, and co-ion exclusion. Results show equilibria with electroneutrality attained through screening and pairing of brush anionic charges by cations. Most surprising is the reversal of the Donnan potential that would be expected based on electrostatic Boltzmann partitioning alone. Water dielectric decrement within the brush domain is also associated with Born hydration-driven cation exclusion from the brush. We observe that the primary partition energy attracting cations to attain brush electroneutrality is the ion-pairing or salt-bridge energy associated with cation-sulfate and cation-carboxylate solvent-separated and contact ion pairs. Potassium and sodium pairing to glycosaminoglycan carboxylates and sulfates consistently show similar abundance of contact-pairing and solvent-separated pairing. In these crowded macromolecular brushes, ion-pairing, Born-hydration, and electrostatic potential energies all contribute to attain electroneutrality and should therefore contribute in mean-field models to accurately represent brush electrostatics.

scholarly journals Insight into the Structure and Dynamics of Polymers by Neutron Scattering Combined with Atomistic Molecular Dynamics Simulations

Polymers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3067
Author(s):  
Arantxa Arbe ◽  
Fernando Alvarez ◽  
Juan Colmenero
Keyword(s):  
Molecular Dynamics ◽  
Neutron Scattering ◽  
Molecular Dynamics Simulations ◽  
Structural Features ◽  
Length Scales ◽  
Polymeric Systems ◽  
Structure And Dynamics ◽  
Dynamical Features ◽  
Dynamics Simulations ◽  
Insight Into

Combining neutron scattering and fully atomistic molecular dynamics simulations allows unraveling structural and dynamical features of polymer melts at different length scales, mainly in the intermolecular and monomeric range. Here we present the methodology developed by us and the results of its application during the last years in a variety of polymers. This methodology is based on two pillars: (i) both techniques cover approximately the same length and time scales and (ii) the classical van Hove formalism allows easily calculating the magnitudes measured by neutron scattering from the simulated atomic trajectories. By direct comparison with experimental results, the simulated cell is validated. Thereafter, the information of the simulations can be exploited, calculating magnitudes that are experimentally inaccessible or extending the parameters range beyond the experimental capabilities. We show how detailed microscopic insight on structural features and dynamical processes of various kinds has been gained in polymeric systems with different degrees of complexity, and how intriguing questions as the collective behavior at intermediate length scales have been faced.

scholarly journals Refinement of a Cryo-EM Structure of hERG: Bridging Structure and Function

2020 ◽  
Author(s):  
H.M. Khan ◽  
J. Guo ◽  
H.J. Duff ◽  
D. P. Tieleman ◽  
S. Y. Noskov
Keyword(s):  
Molecular Dynamics ◽  
High Resolution ◽  
Salt Bridge ◽  
Structure And Function ◽  
Channel Structure ◽  
Salt Bridges ◽  
Voltage Sensing ◽  
Chain Conformations ◽  
And Function ◽  
Voltage Sensing Domain

AbstractThe human ether-a-go-go-related gene (hERG) encodes the voltage gated potassium channel (KCNH2 or Kv11.1, commonly known as hERG). This channel plays a pivotal role in the stability of phase 3 repolarization of the cardiac action potential. Although a high-resolution cryo-EM structure is available for its depolarized (open) state, the structure surprisingly did not feature many functionally important interactions established by previous biochemical and electrophysiology experiments. Using Molecular Dynamics Flexible Fitting (MDFF), we refined the structure and recovered the missing functionally relevant salt bridges in hERG in its depolarized state. We also performed electrophysiology experiments to confirm the functional relevance of a novel salt bridge predicted by our refinement protocol. Our work shows how refinement of a high-resolution cryo-EM structure helps to bridge the existing gap between the structure and function in the voltage-sensing domain (VSD) of hERG.Statement of SignificanceCryo-EM has emerged as a major breakthrough technique in structural biology of membrane proteins. However, even high-resolution Cryo-EM structures contain poor side chain conformations and interatomic clashes. A high-resolution cryo-EM structure of hERG1 has been solved in the depolarized (open) state. The state captured by Cryo-EM surprisingly did not feature many functionally important interactions established by previous experiments. Molecular Dynamics Flexible Fitting (MDFF) used to enable refinement of the hERG1 channel structure in complex membrane environment re-establishing key functional interactions in the voltage sensing domain.

scholarly journals How well do force fields capture the strength of salt bridges in proteins?

2018 ◽  
Author(s):  
Mustapha Carab Ahmed ◽  
Elena Papaleo ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Force Fields ◽  
Salt Bridge ◽  
Salt Bridges ◽  
Enhanced Sampling ◽  
Important Interaction ◽  
Close Proximity ◽  
The Stability ◽  
Dynamics Simulations

AbstractSalt bridges form between pairs of ionisable residues in close proximity and are important interactions in proteins. While salt bridges are known to be important both for protein stability, recognition and regulation, we still do not have fully accurate predictive models to assess the energetic contributions of salt bridges. Molecular dynamics simulations is one technique that may be used study the complex relationship between structure, solvation and energetics of salt bridges, but the accuracy of such simulations depend on the force field used. We have used NMR data on the B1 domain of protein G (GB1) to benchmark molecular dynamics simulations. Using enhanced sampling simulations, we calculated the free energy of forming a salt bridge for three possible ionic interactions in GB1. The NMR experiments showed that these interactions are either not formed, or only very weakly formed, in solution. In contrast, we show that the stability of the salt bridges is slightly overestimated in simulations of GB1 using six commonly used combinations of force fields and water models. We therefore conclude that further work is needed to refine our ability to model quantitatively the stability of salt bridges through simulations, and that comparisons between experiments and simulations will play a crucial role in furthering our understanding of this important interaction.

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