Cosmoplex: Self-consistent Simulation of Self-organizing Inhomogeneous Systems Based on Cosmo-rs

Klamt, Andreas; Koch, Larissa; Terzi, Selman; Huniar, Uwe; Schwöbel, Johannes; Gaudin, Théophile

doi:10.26434/chemrxiv.7218245

Cited by 2 publications

(3 citation statements)

References 5 publications

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“…The authors also demonstrate good agreement with the experimental partition coefficients predicted using the program COSMOmic, an extension of COSMO-RS for anisotropic systems such as micelles and membranes. 263 Rocco et al 264 developed an in silico screen for skin permeability using the relatively old simulation technique of steered molecular dynamics to rapidly probe the response of SC model bilayers to different permeants. Using a learning set of 80 compounds and, in essence, determining the average parameters for the homogenous solubility-diffusion model yielded good correlation of predicted and experimentally determined permeabilities.…”

Section: Kineticmentioning

confidence: 99%

Molecular Dynamics Simulations of Membrane Permeability

2019

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This Review illustrates the evaluation of permeability of lipid membranes from molecular dynamics (MD) simulation primarily using water and oxygen as examples. Membrane entrance, translocation, and exit of these simple permeants (one hydrophilic and one hydrophobic) can be simulated by conventional MD and permeabilities can be evaluated directly by Fick's First Law, transition rates, and a global Bayesian analysis of the inhomogeneous solubility-diffusion model. The assorted results, many of which are applicable to simulations of non-biological membranes, highlight the limitations of the homogeneous solubility diffusion model; support the utility of inhomogeneous solubility diffusion and compartmental models; underscore the need for comparison with experiment for both simple solvent systems (such as water/hexadecane) and well characterized membranes; and demonstrate the need for microsecond simulations for even simple permeants like water and oxygen. Undulations, subdiffusion, fractional viscosity dependence, periodic boundary conditions, and recent developments in the field are also discussed. Lastly, while enhanced sampling methods and increasingly sophisticated treatments of diffusion add substantially to the repertoire of simulation-based approaches, they do not address directly the critical need for force fields with polarizability and multipoles, and constant pH methods.

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Section: Kineticmentioning

confidence: 99%

Molecular Dynamics Simulations of Membrane Permeability

2019

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“…Such an approach was applied in the SMx-based 54,55 and COSMO-based methods. [56][57][58][59][60][61] The anisotropic complexity of the lipid bilayer was approximated by a low-dielectric slab with either isotropic or anisotropic properties along the normal. 62,63 Implicit solvent models have been successfully applied for prediction of transfer free energies and partition coefficients of neutral and ionic solutes from water to organic solvents, micelles, and lipid bilayers.…”

Section: Introductionmentioning

confidence: 99%

“…62,63 Implicit solvent models have been successfully applied for prediction of transfer free energies and partition coefficients of neutral and ionic solutes from water to organic solvents, micelles, and lipid bilayers. 57,60,[62][63][64][65] More recently, physical models of passive membrane permeation based on solubility−diffusion and barrier domain approaches were developed by Leung et al, 32,33 Swift and Amaro, 66,67 and Brocke et al 68 These models assume that the passive membrane permeability primarily depends on the free energy change of barrier crossing, ΔG. The value of ΔG can be calculated as the solvation energy difference between global minimum con formations evaluated in water and in implicit nonpolar organic solvent 32,33 or by integration of transbilayer profiles of the free energy of membrane insertion using heterogeneous dielectric generalized Born (HDGB) or dynamic HDGB (DHGDB) implicit membrane models.…”

Section: Introductionmentioning

confidence: 99%

Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules

Lomize

Pogozheva

2019

J. Chem. Inf. Model.

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Assessment of permeability is a critical step in the drug development process for selection of drug candidates with favorable ADME properties. We have developed a novel physics-based method for fast computational modeling of passive permeation of diverse classes of molecules across lipid membranes. The method is based on heterogeneous solubility−diffusion theory and operates with all-atom 3D structures of solutes and the anisotropic solvent model of the lipid bilayer characterized by transbilayer profiles of dielectric and hydrogen bonding capacity parameters. The optimal translocation pathway of a solute is determined by moving an ensemble of representative conformations of the molecule through the dioleoyl-phosphatidylcholine (DOPC) bilayer and optimizing their rotational orientations in every point of the transmembrane trajectory. The method calculates (1) the membrane-bound state of the solute molecule; (2) free energy profile of the solute along the permeation pathway; and (3) the permeability coefficient obtained by integration over the transbilayer energy profile and assuming a constant size-dependent diffusivity along the membrane normal. The accuracy of the predictions was evaluated against experimental permeability coefficients measured in pure lipid membranes (for 78 compounds, R2 was 0.88 and rmse was 1.15 log units), PAMPA-DS (for 280 compounds, R2 was 0.75 and rmse was 1.59 log units), BBB (for 182 compounds, R2 was 0.69 and rmse was 0.87 log units), and Caco-2/MDCK assays (for 165 compounds, R2 was 0.52 and rmse was 0.89 log units).

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Cosmoplex: Self-consistent Simulation of Self-organizing Inhomogeneous Systems Based on Cosmo-rs

Cited by 2 publications

References 5 publications

Molecular Dynamics Simulations of Membrane Permeability

Molecular Dynamics Simulations of Membrane Permeability

Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules

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