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Statements

Subject Item
n2:RIV%2F61989592%3A15310%2F12%3A33142336%21RIV13-MSM-15310___
rdf:type
skos:Concept n8:Vysledek
dcterms:description
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 mýs MD simulations (total length) and free energy profiles along the bilayer normal calculated by biased MD simulations (7 mýs 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 %22pulling%22 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. 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 mýs MD simulations (total length) and free energy profiles along the bilayer normal calculated by biased MD simulations (7 mýs 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 %22pulling%22 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.
dcterms:title
Convergence of Free Energy Profile of Coumarin in Lipid Bilayer Convergence of Free Energy Profile of Coumarin in Lipid Bilayer
skos:prefLabel
Convergence of Free Energy Profile of Coumarin in Lipid Bilayer Convergence of Free Energy Profile of Coumarin in Lipid Bilayer
skos:notation
RIV/61989592:15310/12:33142336!RIV13-MSM-15310___
n8:predkladatel
n9:orjk%3A15310
n3:aktivita
n16:S n16:P
n3:aktivity
P(ED2.1.00/03.0058), P(EE2.3.20.0017), P(GA303/09/1001), P(GBP208/12/G016), S
n3:cisloPeriodika
4
n3:dodaniDat
n12:2013
n3:domaciTvurceVysledku
n7:3151948 n7:4936094 n7:1410695
n3:druhVysledku
n19:J
n3:duvernostUdaju
n5:S
n3:entitaPredkladatele
n15:predkladatel
n3:idSjednocenehoVysledku
128748
n3:idVysledku
RIV/61989592:15310/12:33142336
n3:jazykVysledku
n13:eng
n3:klicovaSlova
drugs; systems; transport; permeability; intercalants; permeation; mean force; membrane-proteins; computer-simulations; molecular-dynamics simulations
n3:klicoveSlovo
n4:membrane-proteins n4:molecular-dynamics%20simulations n4:permeability n4:permeation n4:systems n4:mean%20force n4:intercalants n4:drugs n4:transport n4:computer-simulations
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[D9216FEA9EAD]
n3:nazevZdroje
Journal of Chemical Theory and Computation
n3:obor
n17:CF
n3:pocetDomacichTvurcuVysledku
3
n3:pocetTvurcuVysledku
3
n3:projekt
n10:EE2.3.20.0017 n10:GBP208%2F12%2FG016 n10:ED2.1.00%2F03.0058 n10:GA303%2F09%2F1001
n3:rokUplatneniVysledku
n12:2012
n3:svazekPeriodika
8
n3:tvurceVysledku
Otyepka, Michal Berka, Karel Paloncýová, Markéta
n3:wos
000302487700005
s:issn
1549-9618
s:numberOfPages
12
n18:doi
10.1021/ct2009208
n20:organizacniJednotka
15310