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Behaviour of small solutes and large drugs in a lipid bilayer from computer simulations

Behaviour of small solutes and large drugs in a lipid bilayer from computer simulations
Behaviour of small solutes and large drugs in a lipid bilayer from computer simulations
To reach their biological target, drugs have to cross cell membranes, and understanding passive membrane permeation is therefore crucial for rational drug design. Molecular dynamics simulations offer a powerful way of studying permeation at the single molecule level. Starting from a computer model proven to be able to reproduce the physical properties of a biological membrane, the behaviour of small solutes and large drugs in a lipid bilayer has been studied. Analysis of dihedral angles shows that a few nanosesconds are sufficient for the simulations to converge towards common values for those angles, even if the starting structures belong to different conformations. Results clearly show that, despite their difference in size, small solutes and large drugs tend to lie parallel to the bilayer normal and that, when moving from water solution into biomembranes, permeants lose degrees of freedom. This explains the experimental observation that partitioning and permeation are highly affected by entropic effects and are size-dependent. Tilted orientations, however, occur when they make possible the formation of hydrogen bonds. This helps to understand the reason why hydrogen bonding possibilities are an important parameter in cruder approaches which predict drug absorption after administration. Interestingly, hydration is found to occur even in the membrane core, which is usually considered an almost hydrophobic region. Simulations suggest the possibility for highly polar compounds like acetic acid to cross biological membranes while hydrated. These simulations prove useful for drug design in rationalising experimental observations and predicting solute behaviour in biomembranes.
molecular dynamics simulation, constraint, beta-blockers, dppc membrane, permeability, molecular-dynamics simulation, surface-area, phospholipid-bilayer, cholesterol bilayers, model membranes, water transport, acetic-acid, n-alkanes, permeation, diffusion
0304-4165
1-21
Bemporad, D.
5b7a45ed-7e84-46a0-b427-e11db4447ca9
Luttmann, C.
3b3767c2-2bc5-4880-b033-963443c6f72a
Essex, J.W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Bemporad, D.
5b7a45ed-7e84-46a0-b427-e11db4447ca9
Luttmann, C.
3b3767c2-2bc5-4880-b033-963443c6f72a
Essex, J.W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

Bemporad, D., Luttmann, C. and Essex, J.W. (2005) Behaviour of small solutes and large drugs in a lipid bilayer from computer simulations. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1718 (1-2), 1-21. (doi:10.1016/j.bbamem.2005.07.009).

Record type: Article

Abstract

To reach their biological target, drugs have to cross cell membranes, and understanding passive membrane permeation is therefore crucial for rational drug design. Molecular dynamics simulations offer a powerful way of studying permeation at the single molecule level. Starting from a computer model proven to be able to reproduce the physical properties of a biological membrane, the behaviour of small solutes and large drugs in a lipid bilayer has been studied. Analysis of dihedral angles shows that a few nanosesconds are sufficient for the simulations to converge towards common values for those angles, even if the starting structures belong to different conformations. Results clearly show that, despite their difference in size, small solutes and large drugs tend to lie parallel to the bilayer normal and that, when moving from water solution into biomembranes, permeants lose degrees of freedom. This explains the experimental observation that partitioning and permeation are highly affected by entropic effects and are size-dependent. Tilted orientations, however, occur when they make possible the formation of hydrogen bonds. This helps to understand the reason why hydrogen bonding possibilities are an important parameter in cruder approaches which predict drug absorption after administration. Interestingly, hydration is found to occur even in the membrane core, which is usually considered an almost hydrophobic region. Simulations suggest the possibility for highly polar compounds like acetic acid to cross biological membranes while hydrated. These simulations prove useful for drug design in rationalising experimental observations and predicting solute behaviour in biomembranes.

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More information

Published date: 10 December 2005
Keywords: molecular dynamics simulation, constraint, beta-blockers, dppc membrane, permeability, molecular-dynamics simulation, surface-area, phospholipid-bilayer, cholesterol bilayers, model membranes, water transport, acetic-acid, n-alkanes, permeation, diffusion

Identifiers

Local EPrints ID: 20721
URI: https://eprints.soton.ac.uk/id/eprint/20721
ISSN: 0304-4165
PURE UUID: e4ccd32e-6fef-4b13-b8fb-b2b28742f892
ORCID for J.W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

Catalogue record

Date deposited: 01 Mar 2006
Last modified: 06 Jun 2018 13:07

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