Comment on “Free energy simulations of single and double ion occupancy in gramicidin A” [J. Chem. Phys. 126, 105103 (2007)]

Roux, Benoı̂t; Andersen, Olaf S.; Allen, Toby W.

doi:10.1063/1.2931568

Cited by 21 publications

(28 citation statements)

References 18 publications

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“…As with the alchemical methods described above, restraining potentials of different shape may be introduced to carry out a calculation, as long as their contributions are correctly accounted for in the final equilibrium binding constant. 70 The PMF-based method is illustrated schematically in Figure 2.…”

Section: Theory and Methodsmentioning

confidence: 99%

Computations of Standard Binding Free Energies with Molecular Dynamics Simulations

2009

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An increasing number of studies have reported computations of the absolute binding free energy of small ligands to proteins using molecular dynamics (MD) simulations with results that are in good agreement with experiments. This encouraging progress suggests that physics-based approaches hold the promise of making important contributions to the process of drug discovery and optimization in the near future. Two types of approaches are principally used to compute binding free energies with MD simulations. The most widely known are based on alchemical free energy methods, in which the interaction of the ligand with its surrounding are progressively switched off. An alternative method is to use a potential of mean force (PMF), in which the ligand is physically separated from the protein receptor. For both of these computational approaches, restraining potentials affecting the translational, rotational and conformational freedom of the ligand and protein may be activated and released during the simulations to aid convergence and improve the sampling. Such restraining potentials add bias to the simulations, but their effects can be rigorously removed to yield a binding free energy that is properly unbiased with respect to the standard state. A review of recent results is presented. Examples of computations with T4-lysozyme mutants, FKBP12, SH2 domain, and cytochrome P450 are discussed and compared. Differences in computational methods are discussed and remaining difficulties and challenges are highlighted.

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Section: Theory and Methodsmentioning

confidence: 99%

Computations of Standard Binding Free Energies with Molecular Dynamics Simulations

2009

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“…The p K a of E148 was estimated using the equation for calculating the equilibrium constant of binding of the substrate at the binding site of the protein, based on the one-dimensional PMF for the substrate moving along the channel axis with the cylindrical potential applied at the channel entrance: 36 where the substrate is the excess proton and the binding site is E148. Here, C 0 is the standard state concentration (1 M = 1/1660 Å –3 ), and Δ G site is the free energy cost introduced by the cylindrical potential at the substrate binding site (the CEC is at E148.).…”

Section: Methodsmentioning

confidence: 99%

The Origin of Coupled Chloride and Proton Transport in a Cl^–/H⁺ Antiporter

et al. 2016

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The ClC family of transmembrane proteins functions throughout nature to control the transport of Cl– ions across biological membranes. ClC-ec1 from Escherichia coli is an antiporter, coupling the transport of Cl– and H+ ions in opposite directions and driven by the concentration gradients of the ions. Despite keen interest in this protein, the molecular mechanism of the Cl–/H+ coupling has not been fully elucidated. Here, we have used multiscale simulation to help identify the essential mechanism of the Cl–/H+ coupling. We find that the highest barrier for proton transport (PT) from the intra- to extracellular solution is attributable to a chemical reaction, the deprotonation of glutamic acid 148 (E148). This barrier is significantly reduced by the binding of Cl– in the “central” site (Cl–cen), which displaces E148 and thereby facilitates its deprotonation. Conversely, in the absence of Cl–cen E148 favors the “down” conformation, which results in a much higher cumulative rotation and deprotonation barrier that effectively blocks PT to the extracellular solution. Thus, the rotation of E148 plays a critical role in defining the Cl–/H+ coupling. As a control, we have also simulated PT in the ClC-ec1 E148A mutant to further understand the role of this residue. Replacement with a non-protonatable residue greatly increases the free energy barrier for PT from E203 to the extracellular solution, explaining the experimental result that PT in E148A is blocked whether or not Cl–cen is present. The results presented here suggest both how a chemical reaction can control the rate of PT and also how it can provide a mechanism for a coupling of the two ion transport processes.

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“…This is needed to construct mathematically well-defined PMFs along the channel axis28,54. Other choices of restraining potential could be used, although the final results will be independent of such choice only if the computations are properly unbiased54.…”

Section: Methodsmentioning

confidence: 99%

Energetics of Double-Ion Occupancy in the Gramicidin A Channel

Andersen

Roux

2010

J. Phys. Chem. B

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To understand the energetics of double ion occupancy in gramicidin A (gA) channels, the 2D potential of mean force (PMF) is calculated for two ions at different positions along the channel axis. The cross sections of this 2D PMF are compared with available 1-ion PMFs to highlight the effect of one ion on the permeation dynamics of the other. It is found that if the first ion stays on one side inside the channel, the second ion has to pass over an additional new barrier to move into the outer binding site on the other side. At the same time both outer and inner binding sites for the second ion become shallower than those in the 1-ion PMF. The calculated ion-ion repulsion for a doubly occupied channel is about 2 kcal/mol, in good agreement with previous experimental estimates. The number of water molecules inside the channel and their dipole moment are calculated to interpret the energetics of double ion occupancy in gA channels. As the first ion moves into the outer binding site and then further into the channel, the oxygen atoms of the single-file water column in the channel is oriented to point toward the ion. The observed dipole moment distribution of a singly occupied channel has only one sharp peak and the water alignment is essentially perfect once the ion is in the inner binding site. For this reason, there is an energy penalty to accomodate a second ion at the opposive end of the channel.

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Comment on “Free energy simulations of single and double ion occupancy in gramicidin A” [J. Chem. Phys. 126, 105103 (2007)]

Cited by 21 publications

References 18 publications

Computations of Standard Binding Free Energies with Molecular Dynamics Simulations

Computations of Standard Binding Free Energies with Molecular Dynamics Simulations

The Origin of Coupled Chloride and Proton Transport in a Cl^–/H⁺ Antiporter

Energetics of Double-Ion Occupancy in the Gramicidin A Channel

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Comment on “Free energy simulations of single and double ion occupancy in gramicidin A” [J. Chem. Phys. 126, 105103 (2007)]

Cited by 21 publications

References 18 publications

Computations of Standard Binding Free Energies with Molecular Dynamics Simulations

Computations of Standard Binding Free Energies with Molecular Dynamics Simulations

The Origin of Coupled Chloride and Proton Transport in a Cl–/H+ Antiporter

Energetics of Double-Ion Occupancy in the Gramicidin A Channel

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The Origin of Coupled Chloride and Proton Transport in a Cl^–/H⁺ Antiporter