Behaviour of small solutes and large drugs in a lipid bilayer from computer simulations
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)
Download
Full text not available from this repository.
Official URL: http://dx.doi.org/10.1016/j.bbamem.2005.07.009
Description/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.
| Item Type: | Article |
|---|---|
| ISSN: | 0006-3002 (print) |
| Uncontrolled 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 |
| Related URLs: | http://www.ncbi.nlm.nih.gov/en...med_docsum http://dx.doi.org/10.1016/j.bb...005.07.009 |
| Subjects: | Q Science > QD Chemistry |
| Divisions: | University Structure - Pre August 2011 > School of Chemistry |
| ePrint ID: | 20721 |
| URI: | http://eprints.soton.ac.uk/id/eprint/20721 |
| Deposited On: | 01 Mar 2006 |
| Last Modified: | 01 May 2012 02:18 |
Associated Staff Only: edit my ePrint
