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- Biggin, P
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Philip Biggin is the RCUK Fellow in Structural Bioinformatics in the Department of Biochemistry at the University of Oxford. He read computer-aided chemistry at the University of Surrey before undertaking a D.Phil in Molecular Biophysics at the University of Oxford. After post-doctoral work at the Salk Institute in California he returned to Oxford. His research interests lie in receptor-ligand interactions, viral ion channels, comparative dynamics of proteins and bioinformatics of ligand-gated ion channels. He is a co-opted committee member of the Molecular Graphics and Modelling Society and a member of the Royal Society of Chemistry, the British Biophysical Society, the Biochemical Society, andthe US Biophysical Society.
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Drug interaction and permeation in lipid bilayers: Amantadine as a test case
Philip Biggin, Oxford University
Amantadine is a drug that has found use in the treatment of influenza A and Parkinson’s disease amongst others. The mode of action for influenza A is based upon its interaction with the trans-membrane M2 protein channel. An understanding of how amantadine (and related compounds) interact with the lipid bilayer is thus of great interest. We have used molecular dynamics simulations to calculate the potential of mean force of amantadine through a lipid bilayer. Our results demonstrate a preference for the interfacial region of the lipid bilayer for both protonated and deprotonated species. The protonated species is energetically more favourable for this position than the deprotonated which stems from electrostatic interactions with the lipid head-group – the glycerol oxygens in particular. However, the protonated species has a large barrier in the centre of the bilayer and although some of the energetic cost is reduced by bilayer deformation and water penetration, it is too high to allow effective permeation. In contrast there is no barrier (compared to aqueous solution) at the centre ofthe bilayer for the deprotonated species, suggesting that the permeant species is indeed the neutral form as commonly assumed. We have also calculated the partition coefficient (40 ± 2.3) which is in excellent agreement with the reported partition coefficient (37.8 ± 0.4) from arecent NMR study. Note that these partition coefficients are considerably higher than bulk hydrocarbon solvent (typically about 2). Although the protonated form will not readily permeate, its interaction with the interface must be considered as most of amantadine in solution will be protonated (pkA 9) at neutral pH. Thus these sorts of calculations can helpdissect out the finer points of drug-lipid interactions.
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