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Convergence of Free Energy Profile of Coumarin in Lipid Bilayer

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      Atomistic molecular dynamics (MD) simulations of druglike molecules embedded in lipid bilayers are of considerable interest as models for drug penetration and positioning in biological membranes. Here we analyze partitioning of coumarin in dioleoylphosphatidylcholine (DOPC) bilayer, based on both multiple, unbiased 3 μs MD simulations (total length) and free energy profiles along the bilayer normal calculated by biased MD simulations (∼7 μs in total). The convergences in time of free energy profiles calculated by both umbrella sampling and z-constraint techniques are thoroughly analyzed. Two sets of starting structures are also considered, one from unbiased MD simulation and the other from “pulling” coumarin along the bilayer normal. The structures obtained by pulling simulation contain water defects on the lipid bilayer surface, while those acquired from unbiased simulation have no membrane defects. The free energy profiles converge more rapidly when starting frames from unbiased simulations are used. In addition, z-constraint simulation leads to more rapid convergence than umbrella sampling, due to quicker relaxation of membrane defects. Furthermore, we show that the choice of RESP, PRODRG, or Mulliken charges considerably affects the resulting free energy profile of our model drug along the bilayer normal. We recommend using z-constraint biased MD simulations based on starting geometries acquired from unbiased MD simulations for efficient calculation of convergent free energy profiles of druglike molecules along bilayer normals. The calculation of free energy profile should start with an unbiased simulation, though the polar molecules might need a slow pulling afterward. Results obtained with the recommended simulation protocol agree well with available experimental data for two coumarin derivatives.

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        Canonical sampling through velocity-rescaling

        We present a new molecular dynamics algorithm for sampling the canonical distribution. In this approach the velocities of all the particles are rescaled by a properly chosen random factor. The algorithm is formally justified and it is shown that, in spite of its stochastic nature, a quantity can still be defined that remains constant during the evolution. In numerical applications this quantity can be used to measure the accuracy of the sampling. We illustrate the properties of this new method on Lennard-Jones and TIP4P water models in the solid and liquid phases. Its performance is excellent and largely independent on the thermostat parameter also with regard to the dynamic properties.
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            Author and article information

            []Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, simplePalacky University , tr. 17 listopadu 12, 771 46, Olomouc, Czech Republic
            Author notes
            J Chem Theory Comput
            J Chem Theory Comput
            Journal of Chemical Theory and Computation
            American Chemical Society
            24 February 2012
            10 April 2012
            : 8
            : 4
            : 1200-1211
            Copyright © 2012 American Chemical Society

            This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at

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            Computational chemistry & Modeling


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