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Permeability of drugs and hormones through a lipid bilayer: insights from dual-resolution molecular dynamics

Permeability of drugs and hormones through a lipid bilayer: insights from dual-resolution molecular dynamics
Permeability of drugs and hormones through a lipid bilayer: insights from dual-resolution molecular dynamics
The unassisted permeation process of ?-blocker drugs (alprenolol, atenolol, pindolol) and steroid hormones (progesterone, testosterone) through a lipid membrane is simulated by a novel dual-resolution molecular dynamics approach. The lipid and water molecules are described by simple and efficient coarse-grain models, whereas the drug and hormone permeants are represented by traditional atomistic models. Our hybrid method is about two orders of magnitude faster than standard atomic-level counterparts. For each permeant, we calculate the transfer free energy as a function of depth inside the bilayer; these data indicate the location across the membrane where the solutes preferentially partition. Using the free energy profiles, we develop a simple expression that proves remarkably accurate in predicting experimental permeability rankings; the proposed permeation model highlights and addresses potentially problematic aspects of the standard solubility-diffusion theory. We also calculate the diffusion coefficients of the permeants, and track their lateral motion to study their diffusive patterns. Furthermore, we show the drugs' perturbing effect on the bilayer structure and quantify the steroids' preferred orientations. The results obtained compare favourably with experimental measurements and traditional atomic-level simulation data reported in the literature. Promising potential applications of our methodology to areas such as drug design and membrane-protein modelling are discussed
1744-683X
3797-3808
Orsi, Mario
62904259-9a93-4d02-8ce6-d8ef53dfcbf1
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Orsi, Mario
62904259-9a93-4d02-8ce6-d8ef53dfcbf1
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

Orsi, Mario and Essex, Jonathan W. (2010) Permeability of drugs and hormones through a lipid bilayer: insights from dual-resolution molecular dynamics. Soft Matter, 6 (16), 3797-3808. (doi:10.1039/c0sm00136h).

Record type: Article

Abstract

The unassisted permeation process of ?-blocker drugs (alprenolol, atenolol, pindolol) and steroid hormones (progesterone, testosterone) through a lipid membrane is simulated by a novel dual-resolution molecular dynamics approach. The lipid and water molecules are described by simple and efficient coarse-grain models, whereas the drug and hormone permeants are represented by traditional atomistic models. Our hybrid method is about two orders of magnitude faster than standard atomic-level counterparts. For each permeant, we calculate the transfer free energy as a function of depth inside the bilayer; these data indicate the location across the membrane where the solutes preferentially partition. Using the free energy profiles, we develop a simple expression that proves remarkably accurate in predicting experimental permeability rankings; the proposed permeation model highlights and addresses potentially problematic aspects of the standard solubility-diffusion theory. We also calculate the diffusion coefficients of the permeants, and track their lateral motion to study their diffusive patterns. Furthermore, we show the drugs' perturbing effect on the bilayer structure and quantify the steroids' preferred orientations. The results obtained compare favourably with experimental measurements and traditional atomic-level simulation data reported in the literature. Promising potential applications of our methodology to areas such as drug design and membrane-protein modelling are discussed

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Published date: 2010

Identifiers

Local EPrints ID: 179879
URI: http://eprints.soton.ac.uk/id/eprint/179879
ISSN: 1744-683X
PURE UUID: 31704a42-f4ab-4e22-8d33-a6cfd88833c7
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 04 Apr 2011 14:32
Last modified: 10 Dec 2019 01:55

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