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Calculating kinetic rates and membrane permeability from biased simulation.

Badaoui, Magd and Kells, Adam and Molteni, Carla and Dickson, Callum and Hornak, Viktor and Rosta, Edina (2018) Calculating kinetic rates and membrane permeability from biased simulation. The Journal of Physical Chemistry B. ISSN 1520-61061520-5207

Abstract

We present a simple approach to calculate the kinetic properties of lipid membrane crossing processes from biased molecular dynamics simulations. We demonstrate that by using biased simulations, one can obtain highly accurate kinetic information with significantly reduced computational time. We describe how to conveniently calculate the transition rates to enter, cross and exit the membrane in terms of mean first passage times. By constructing a Markov model from the biased data using the Dynamic Histogram Analysis Method, the spectral properties of the resultant model allow for the easy calculation of free energy barriers and relaxation times. The permeability coefficients that are calculated from the relaxation times are found to correlate highly with experimentally calculated values. We show that more generally, certain calculated kinetic properties linked to the crossing of the membrane layer (e.g., barrier height, barrier crossing rates etc) are good indicators of ordering drugs by permeability. Extending the analysis to a 2-D Markov model allows for a physical description of the membrane crossing mechanism.

Item Type: Article
Date Deposited: 13 Oct 2018 00:45
Last Modified: 13 Oct 2018 00:45
URI: https://oak.novartis.com/id/eprint/37021

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