The Experts below are selected from a list of 14502 Experts worldwide ranked by ideXlab platform
Timothy A Cross - One of the best experts on this subject based on the ideXlab platform.
-
CompArison of GrAmicidin A And GrAmicidin M chAnnel conductAnce dispersities.
Biochimica et Biophysica Acta, 2001Co-Authors: Jeffrey C. Markham, Joseph A. Gowen, Timothy A Cross, David Don BusathAbstract:AbstrAct To explore the possible role of Trp side chAins in GrAmicidin chAnnel conductAnce dispersity, we studied the dispersity of GrAmicidin M (gM), A GrAmicidin vAriAnt in which All four tryptophAn residues Are replAced with phenylAlAnine residues, And its enAntiomer, GrAmicidin M− (gM−), And compAred them to thAt of GrAmicidin A (gA). The conductAnces of highly purified gM And gM− were studied in AlkAli metAl solutions At A vAriety of concentrAtions And voltAges, in seven different types of lipid, And in the presence of detergent. Like gA chAnnels, the most common gM chAnnel conductAnce forms A nArrow bAnd. However, unlike gA chAnnels, where the remAining 5–30% of chAnnel conductAnces Are broAdly distributed below (And slightly Above) the mAin bAnd, in gM there is A nArrow secondAry bAnd with
-
vAlidAtion of the single strAnded chAnnel conformAtion of GrAmicidin A by solid stAte nmr
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: F A Kovacs, Jack R. Quine, Timothy A CrossAbstract:AbstrAct The monovAlent cAtion selective chAnnel formed by A dimer of the polypeptide GrAmicidin A hAs A single-strAnded, right-hAnded helicAl motif with 6.5 residues per turn forming A 4-A diAmeter pore. The structure hAs been refined to high resolution AgAinst 120 orientAtionAl constrAints obtAined from sAmples in A liquid-crystAlline phAse lipid bilAyer. These structurAl constrAints from solid-stAte NMR reflect the orientAtion of spin interAction tensors with respect to A unique moleculAr Axis. BecAuse these tensors Are fixed in the moleculAr frAme And becAuse the sAmples Are uniformly Aligned with respect to the mAgnetic field of the NMR spectrometer, eAch constrAint restricts the orientAtion of internucleAr vectors with respect to the lAborAtory frAme of reference. The structurAl motif of this chAnnel hAs been vAlidAted, And the high-resolution structure hAs led to precise models for cAtion binding, cAtion selectivity, And cAtion conductAnce efficiency. The structure is consistent with the electrophysiologicAl dAtA And numerous biophysicAl studies. ContrAry to A recent clAim [BurkhArt, B. M., Li, N., LAngs, D. A., PAngborn, W. A. & DuAx, W. L. (1998) Proc. NAtl. AcAd. Sci. USA 95, 12950–12955], the solid-stAte NMR constrAints for GrAmicidin A in A lipid bilAyer Are not consistent with An x-rAy crystAllogrAphic structure for GrAmicidin hAving A double-strAnded, right-hAnded helix with 7.2 residues per turn.
-
high resolution conformAtion of GrAmicidin A in A lipid bilAyer by solid stAte nmr
Science, 1993Co-Authors: Randal R Ketchem, W Hu, Timothy A CrossAbstract:Solid-stAte nucleAr mAgnetic resonAnce spectroscopy of uniformly Aligned prepArAtions of GrAmicidin A in lipid bilAyers hAs been used to elucidAte A high-resolution dimeric structure of the cAtion chAnnel conformAtion solely on the bAsis of the Amino Acid sequence And 144 orientAtionAl constrAints. This initiAl structure defines the helicAl pitch As single-strAnded, fixes the number of residues per turn At six to seven, specifies the helix sense As right-hAnded, And identifies the hydrogen bonds. Refinement of this initiAl structure yields reAsonAble hydrogen-bonding distAnces with only minimAl chAnges in the torsion Angles.
-
A conformAtionAl reArrAngement in GrAmicidin A: from A double-strAnded left-hAnded to A single-strAnded right-hAnded helix.
Biochemistry, 1992Co-Authors: Zhenlu Zhang, Steven M. Pascal, Timothy A CrossAbstract:A conformAtionAl trAnsition is described for the polypeptide, GrAmicidin A, in which A dimer thAt forms A left-hAnded intertwined AntipArAllel helix is converted to A single-strAnded Amino terminus to Amino terminus right-hAnded helix. The stArting structure is determined here by solution NMR methods while reference is mAde to the well-estAblished folding motif of GrAmicidin in A lipid bilAyer for the ultimAte conformAtion of this trAnsition. Furthermore, An orgAnic solvent system of benzene And ethAnol in which GrAmicidin hAs A unique conformAtion is identified. This conformAtion is shown to be very similAr to thAt derived from X-rAy diffrAction of crystAls prepAred from A similAr solvent system.
Serdar Kuyucak - One of the best experts on this subject based on the ideXlab platform.
-
free energy simulAtions of single And double ion occupAncy in GrAmicidin A
Journal of Chemical Physics, 2007Co-Authors: Turgut Bastug, Serdar KuyucakAbstract:SimultAneous occupAncy of the two binding sites in GrAmicidin A by monovAlent cAtions is A well known property of this chAnnel, but the energetic feAsibility of this process in moleculAr dynAmics simulAtions hAs not been estAblished so fAr. Here the Authors study the energetics of single And double ion occupAncy in GrAmicidin A by constructing the potentiAl of meAn force for single And pAir of cAtions. As representAtives of smAll And lArge ions, they consider both NA+ And K+ ions in the cAlculAtions. Binding constAnts of ions Are estimAted from the free energy profiles. CompArisons with the experimentAl results indicAte 3–4kT discrepAncy in the binding energies. They Also study the coordinAtion of the ions in their respective binding sites And the dynAmic behAvior of the chAnnel wAter during the double ion binding process.
-
energetics of ion permeAtion rejection binding And block in GrAmicidin A from free energy simulAtions
Biophysical Journal, 2006Co-Authors: Turgut Bastug, Serdar KuyucakAbstract:The rigid force fields currently used in moleculAr dynAmics (MD) simulAtions of biomolecules Are optimized for globulAr proteins. Whether they cAn Also be used in MD simulAtions of membrAne proteins is An importAnt issue thAt needs to be resolved. Here we Address this issue using the GrAmicidin A chAnnel, which provides An ideAl test cAse becAuse of the simplicity of its structure And the AvAilAbility of A weAlth of functionAl dAtA. PermeAtion properties of GrAmicidin A cAn be summArized As “it conducts monovAlent cAtions, rejects Anions, And binds divAlent cAtions.” Hence, A comprehensive test should consider the energetics of permeAtion for All three types of ions. To thAt end, we construct the potentiAl of meAn force for K+, Cl−, And CA2+ ions Along the chAnnel Axis. For An independent check of the potentiAl-of-meAn-force results, we Also cAlculAte the free energy differences for these ions At the chAnnel center And binding sites relAtive to bulk. We find thAt “rejection of Anions” is sAtisfied but there Are difficulties in AccommodAting the other two properties using the current MD force fields.
-
role of protein flexibility in ion permeAtion A cAse study in GrAmicidin A
Biophysical Journal, 2006Co-Authors: Turgut Bastug, Angus Grayweale, Swarna M Patra, Serdar KuyucakAbstract:Proteins hAve A flexible structure, And their Atoms exhibit considerAble fluctuAtions under normAl operAting conditions. However, ApArt from some enzyme reActions involving ligAnd binding, our understAnding of the role of flexibility in protein function remAins mostly incomplete. Here we investigAte this question in the reAlm of membrAne proteins thAt form ion chAnnels. SpecificAlly, we consider ion permeAtion in the GrAmicidin A chAnnel, And study how the energetics of ion conduction chAnges As the chAnnel structure is progressively chAnged from completely flexible to A fixed one. For eAch chAnnel structure, the potentiAl of meAn force for A permeAting potAssium ion is determined from moleculAr dynAmics (MD) simulAtions. Using the sAme moleculAr dynAmics dAtA for completely flexible GrAmicidin A, we Also cAlculAte the AverAge densities And fluctuAtions of the peptide Atoms And investigAte the correlAtions between these fluctuAtions And the motion of A permeAting ion. Our results show conclusively thAt peptide flexibility plAys An importAnt role in ion permeAtion in the GrAmicidin A chAnnel, thus providing Another reAson—besides the well-known problem with the description of single file pore wAter—why this chAnnel cAnnot be modeled using continuum electrostAtics with A fixed structure. The new method developed here for studying the role of protein flexibility on its function clArifies the contributions of the fluctuAtions to energy And entropy, And plAces limits on the level of detAil required in A coArse-grAined model.
-
GrAmicidin A chAnnel As A test ground for moleculAr dynAmics force fields
Biophysical Journal, 2003Co-Authors: Toby W Allen, Turgut Bastug, Serdar Kuyucak, Shinho ChungAbstract:We use the well-known structurAl And functionAl properties of the GrAmicidin A chAnnel to test the AppropriAteness of force fields commonly used in moleculAr dynAmics (MD) simulAtions of ion chAnnels. For this purpose, the high-resolution structure of the GrAmicidin A dimer is embedded in A dimyristoylphosphAtidylcholine bilAyer, And the potentiAl of meAn force of A K+ ion is cAlculAted Along the chAnnel Axis using the umbrellA sAmpling method. CAlculAtions Are performed using two of the most common force fields in MD simulAtions: CHARMM And GROMACS. Both force fields leAd to lArge centrAl bArriers for K+ ion permeAtion, thAt Are substAntiAlly higher thAn those deduced from the physiologicAl dAtA by inverse methods. In long MD simulAtions lAsting over 60 ns, severAl ions Are observed to enter the binding site but none of them crossed the chAnnel despite the presence of A lArge driving field. The present results, tAken together with mAny eArlier studies, highlights the shortcomings of the stAndArd force fields used in MD simulAtions of ion chAnnels And cAlls for construction of more AppropriAte force fields for this purpose.
Yuri N. Antonenko - One of the best experts on this subject based on the ideXlab platform.
-
membrAne elAstic deformAtions modulAte GrAmicidin A trAnsbilAyer dimerizAtion And lAterAl clustering
Biophysical Journal, 2018Co-Authors: Oleg V Kondrashov, Timur R Galimzyanov, Konstantin V Pavlov, Sergey A Akimov, Elena A. Kotova, Yuri N. AntonenkoAbstract:GrAmicidin A (gA) is A short β-helicAl peptide known to form conducting chAnnels in lipid membrAnes becAuse of trAnsbilAyer dimerizAtion. The gA conducting dimer, being shorter thAn the lipid bilAyer thickness, deforms the membrAne in its vicinity, And the bilAyer elAstic energy contributes to the gA dimer formAtion energy. Likewise, membrAne incorporAtion of A gA monomer, which is shorter thAn the lipid monolAyer thickness, creAtes A void, thereby forcing surrounding lipid molecules to tilt to fill it. The energy of membrAne deformAtion wAs cAlculAted in the frAmework of the continuum elAsticity theory, tAking into Account splAy, tilt, lAterAl stretching/compression, GAussiAn splAy deformAtions, And externAl membrAne tension. We obtAined the interAction energy profiles for two gA monomers locAted either in the sAme or in the opposite monolAyers. The profiles demonstrAted the long-rAnge AttrAction And short-rAnge repulsion behAvior of the monomers resulting from the membrAne deformAtion. AnAlysis of the profile feAtures reveAled conditions under which clusters of gA monomers would not dissipAte becAuse of diffusion. The cAlculAted dependence of the dimer formAtion And decAy energy bArriers on the membrAne elAstic properties wAs in good Agreement with the AvAilAble experimentAl dAtA And suggested An explAnAtion for A hitherto contentious phenomenon.
-
ph dependent properties of ion chAnnels formed by n terminAlly glutAmAte substituted GrAmicidin A in plAnAr lipid bilAyers
Biochimica et Biophysica Acta, 2017Co-Authors: Sergey I Kovalchuk, Dmitry K Chistyulin, Alexandra I Sorochkina, Tatyana I. Rokitskaya, Alexander M. Firsov, Elena A. Kotova, Yuri N. AntonenkoAbstract:AbstrAct The N-terminAlly glutAmAte substituted AnAlogue of the pentAdecApeptide GrAmicidin A [Glu1]gA hAs been previously described As A low-toxic uncoupler of mitochondriAl oxidAtive phosphorylAtion And neuroprotector. Here, we studied ion chAnnel-forming Activity of this peptide in plAnAr bilAyer lipid membrAnes (BLMs). [Glu1]gA exhibited An Ability to induce both mAcroscopic current And single chAnnels in A broAd pH rAnge, Albeit with A lower potency thAn the pArent GrAmicidin A (gA). Single-chAnnel recordings in 1 M KCl At pH About 4 showed chAnnel openings of one type with the conductAnce (About 26 pS), similAr to thAt of gA, And the lifetime (40 ms), much shorter thAn thAt of gA. By contrAst, two populAtions of chAnnels were found At pH 9, one of which hAd much longer durAtion (severAl seconds) And lower conductAnce (3.5–10 pS). AutocorrelAtion function of the current noise of [Glu1]gA reveAled A mArked shift towArds longer correlAtion times upon AlkAlinizAtion. The sensitized photoinActivAtion technique Also reveAled substAntiAl differences in [Glu1]gA conducting properties At AlkAline And Acidic pH, in pArticulAr decelerAtion of the photoinActivAtion kinetics And A shArp decreAse in its Amplitude upon AlkAlinizAtion. A double-logArithmic plot of the concentrAtion dependence of [Glu1]gA-induced BLM conductAnce hAd the slope of About 3, which pointed to peptide AggregAtion in the membrAne. The dAtA were discussed in relAtion to pH-dependent AggregAtion of [Glu1]gA, resulting from deprotonAtion of the glutAmAte side chAin At AlkAline pH.
-
neuroprotective effect of glutAmAte substituted AnAlog of GrAmicidin A is mediAted by the uncoupling of mitochondriA
Biochimica et Biophysica Acta, 2014Co-Authors: D N Silachev, L S Khailova, V A Babenko, Mikhail V. Gulyaev, Sergey I Kovalchuk, L D Zorova, Egor Y Plotnikov, Yuri N. Antonenko, Dmitry B. ZorovAbstract:AbstrAct BAckground ReActive oxygen species Are grossly produced in the brAin After cerebrAl ischemiA And reperfusion cAusing neuronAl cell deAth. MitochondriAl production of reActive oxygen species is nonlineArly relAted to the vAlue of the mitochondriAl membrAne potentiAl with significAnt increment At vAlues exceeding 150 mV. Therefore, limited uncoupling of oxidAtive phosphorylAtion could be beneficiAl for cells exposed to deleterious oxidAtive stress-AssociAted conditions by preventing excessive generAtion of reActive oxygen species. Methods Protonophoric And uncoupling Activities of different peptides were meAsured using pyrAnine-loAded liposomes And isolAted mitochondriA. To evAluAte the effect of glutAmAte-substituted AnAlog of GrAmicidin A ([Glu1]gA) AdministrAtion on the brAin ischemic dAmAge, we employed the in vitro model of neuronAl hypoxiA using primAry neuronAl cell cultures And the in vivo model of cerebrAl ischemiA induced in rAts by the middle cerebrAl Artery occlusion. Results [Glu1]gA wAs the most effective in proton-trAnsferring Activity Among severAl N-terminAlly substituted AnAlogs of GrAmicidin A tested in liposomes And rAt brAin And liver mitochondriA. The peptides were found to be protective AgAinst ischemiA-induced neuronAl cell deAth And they lowered mitochondriAl membrAne potentiAl in cultured neurons And diminished reActive oxygen species production in isolAted brAin mitochondriA. The intrAnAsAl AdministrAtion of [Glu1]gA remArkAbly diminished the infArct size indicAted in MR-imAges of A brAin At dAy 1 After the middle cerebrAl Artery occlusion. In [Glu1]gA-treAted rAts, the ischemiA-induced brAin swelling And behAviorAl dysfunction were significAntly suppressed. Conclusions The glutAmAte-substituted AnAlogs of GrAmicidin A displAying protonophoric And uncoupling Activities protect neurAl cells And the brAin from the injury cAused by ischemiA/reperfusion. GenerAl significAnce [Glu1]gA mAy be potentiAlly used As A therApeutic Agent to prevent neuron dAmAge After stroke.
-
Ion chAnnels of vArious types induced in lipid membrAnes by GrAmicidin A derivAtives cArrying A cAtionic sequence At their C-termini
Russian Journal of Bioorganic Chemistry, 2007Co-Authors: T. B. Stoilova, Yuri N. Antonenko, E. A. Dutseva, A. A. Pashkovskaya, S. V. Sychev, S. I. Koval’chuk, A. A. Sobko, N. S. Egorova, E. A. Kotova, A. Yu. SurovoiAbstract:The chAnnel-forming Activity of GrAmicidin A derivAtives cArrying positively chArged Amino Acid sequences At their C -termini wAs studied on plAnAr bilAyer lipid membrAnes And liposomes. We showed previously (FEBS Lett., 2005, vol. 579, pp. 5247–5252) thAt, At low concentrAtions, these peptides form clAssicAl cAtion-selective pores typicAl of GrAmicidin A, whereAs, At high concentrAtions, they form lArge nonselective pores. The Ability of the peptides to form nonselective pores, which wAs determined by the efflux of cArboxyfluorescein, An orgAnic dye, from liposomes, decreAsed substAntiAlly As the length of the GrAmicidin frAgment in the series of cAtionic AnAlogues wAs truncAted. CD spectrA showed thAt lArge pores Are formed by peptides hAving both β^6.3 single-strAnded And β^5.6 double-strAnded helicAl conformAtions of the GrAmicidin frAgment, with the C -terminAl cAtionic sequence being extended. The dimerizAtion of the peptides by the oxidAtion of the terminAl cysteine promoted the formAtion of nonselective pores. It wAs shown thAt nonselective pores Are not formed in membrAnes of erythrocytes, which mAy indicAte A dependence of the chAnnel-forming Ability on the membrAne type. The results mAy be of interest for the directed synthesis of peptides with AntibActeriAl Activity.
-
Effect of GrAmicidin A on the dipole potentiAl of phospholipid membrAnes.
Biophysical Journal, 1999Co-Authors: Vladimir L. Shapovalov, Tatyana I. Rokitskaya, Elena A. Kotova, Yuri N. AntonenkoAbstract:The effect of chAnnel-forming peptide GrAmicidin A on the dipole potentiAl of phospholipid monolAyers And bilAyers hAs been studied. SurfAce pressure And surfAce potentiAl isotherms of monolAyers hAve been meAsured with A LAngmuir trough equipped with A Wilhelmy bAlAnce And A surfAce potentiAl meter (Kelvin probe). GrAmicidin hAs been shown to shift pressure-AreA isotherms of phospholipids And to reduce their monolAyer surfAce potentiAls. Both effects increAse with the increAse in GrAmicidin concentrAtion And depend on the kind of phosphAtidylcholine used. ApplicAtion of the duAl-wAvelength rAtiometric fluorescence method using the potentiAl-sensitive dye RH421 hAs reveAled thAt the Addition of GrAmicidin A to dipAlmitoylphosphAtidylcholine liposomes leAds to A decreAse in the fluorescence rAtio of RH421. This is similAr to the effect of phloretin, which is known to decreAse the dipole potentiAl. The compArison of the concentrAtion dependences of the fluorescence rAtio for GrAmicidin And phloretin shows thAt GrAmicidin is As potent As phloretin in modifying the membrAne dipole potentiAl.
Turgut Bastug - One of the best experts on this subject based on the ideXlab platform.
-
free energy simulAtions of single And double ion occupAncy in GrAmicidin A
Journal of Chemical Physics, 2007Co-Authors: Turgut Bastug, Serdar KuyucakAbstract:SimultAneous occupAncy of the two binding sites in GrAmicidin A by monovAlent cAtions is A well known property of this chAnnel, but the energetic feAsibility of this process in moleculAr dynAmics simulAtions hAs not been estAblished so fAr. Here the Authors study the energetics of single And double ion occupAncy in GrAmicidin A by constructing the potentiAl of meAn force for single And pAir of cAtions. As representAtives of smAll And lArge ions, they consider both NA+ And K+ ions in the cAlculAtions. Binding constAnts of ions Are estimAted from the free energy profiles. CompArisons with the experimentAl results indicAte 3–4kT discrepAncy in the binding energies. They Also study the coordinAtion of the ions in their respective binding sites And the dynAmic behAvior of the chAnnel wAter during the double ion binding process.
-
energetics of ion permeAtion rejection binding And block in GrAmicidin A from free energy simulAtions
Biophysical Journal, 2006Co-Authors: Turgut Bastug, Serdar KuyucakAbstract:The rigid force fields currently used in moleculAr dynAmics (MD) simulAtions of biomolecules Are optimized for globulAr proteins. Whether they cAn Also be used in MD simulAtions of membrAne proteins is An importAnt issue thAt needs to be resolved. Here we Address this issue using the GrAmicidin A chAnnel, which provides An ideAl test cAse becAuse of the simplicity of its structure And the AvAilAbility of A weAlth of functionAl dAtA. PermeAtion properties of GrAmicidin A cAn be summArized As “it conducts monovAlent cAtions, rejects Anions, And binds divAlent cAtions.” Hence, A comprehensive test should consider the energetics of permeAtion for All three types of ions. To thAt end, we construct the potentiAl of meAn force for K+, Cl−, And CA2+ ions Along the chAnnel Axis. For An independent check of the potentiAl-of-meAn-force results, we Also cAlculAte the free energy differences for these ions At the chAnnel center And binding sites relAtive to bulk. We find thAt “rejection of Anions” is sAtisfied but there Are difficulties in AccommodAting the other two properties using the current MD force fields.
-
role of protein flexibility in ion permeAtion A cAse study in GrAmicidin A
Biophysical Journal, 2006Co-Authors: Turgut Bastug, Angus Grayweale, Swarna M Patra, Serdar KuyucakAbstract:Proteins hAve A flexible structure, And their Atoms exhibit considerAble fluctuAtions under normAl operAting conditions. However, ApArt from some enzyme reActions involving ligAnd binding, our understAnding of the role of flexibility in protein function remAins mostly incomplete. Here we investigAte this question in the reAlm of membrAne proteins thAt form ion chAnnels. SpecificAlly, we consider ion permeAtion in the GrAmicidin A chAnnel, And study how the energetics of ion conduction chAnges As the chAnnel structure is progressively chAnged from completely flexible to A fixed one. For eAch chAnnel structure, the potentiAl of meAn force for A permeAting potAssium ion is determined from moleculAr dynAmics (MD) simulAtions. Using the sAme moleculAr dynAmics dAtA for completely flexible GrAmicidin A, we Also cAlculAte the AverAge densities And fluctuAtions of the peptide Atoms And investigAte the correlAtions between these fluctuAtions And the motion of A permeAting ion. Our results show conclusively thAt peptide flexibility plAys An importAnt role in ion permeAtion in the GrAmicidin A chAnnel, thus providing Another reAson—besides the well-known problem with the description of single file pore wAter—why this chAnnel cAnnot be modeled using continuum electrostAtics with A fixed structure. The new method developed here for studying the role of protein flexibility on its function clArifies the contributions of the fluctuAtions to energy And entropy, And plAces limits on the level of detAil required in A coArse-grAined model.
-
GrAmicidin A chAnnel As A test ground for moleculAr dynAmics force fields
Biophysical Journal, 2003Co-Authors: Toby W Allen, Turgut Bastug, Serdar Kuyucak, Shinho ChungAbstract:We use the well-known structurAl And functionAl properties of the GrAmicidin A chAnnel to test the AppropriAteness of force fields commonly used in moleculAr dynAmics (MD) simulAtions of ion chAnnels. For this purpose, the high-resolution structure of the GrAmicidin A dimer is embedded in A dimyristoylphosphAtidylcholine bilAyer, And the potentiAl of meAn force of A K+ ion is cAlculAted Along the chAnnel Axis using the umbrellA sAmpling method. CAlculAtions Are performed using two of the most common force fields in MD simulAtions: CHARMM And GROMACS. Both force fields leAd to lArge centrAl bArriers for K+ ion permeAtion, thAt Are substAntiAlly higher thAn those deduced from the physiologicAl dAtA by inverse methods. In long MD simulAtions lAsting over 60 ns, severAl ions Are observed to enter the binding site but none of them crossed the chAnnel despite the presence of A lArge driving field. The present results, tAken together with mAny eArlier studies, highlights the shortcomings of the stAndArd force fields used in MD simulAtions of ion chAnnels And cAlls for construction of more AppropriAte force fields for this purpose.
Shinho Chung - One of the best experts on this subject based on the ideXlab platform.
-
Influence of protein flexibility on the electrostAtic energy lAndscApe in GrAmicidin A
European Biophysics Journal, 2005Co-Authors: Ben Corry, Shinho ChungAbstract:We describe An electrostAtic model of the GrAmicidin A chAnnel thAt Allows protein Atoms to move in response to the presence of A permeAting ion. To do this, moleculAr dynAmics simulAtions Are cArried out with A permeAting ion At vArious positions within the chAnnel. Then An ensemble of Atomic coordinAtes tAken from the simulAtions Are used to construct energy profiles using mAcroscopic electrostAtic cAlculAtions. The energy profiles constructed Are compAred to experimentAlly-determined conductAnce dAtA by inserting them into BrowniAn dynAmics simulAtions. We find thAt the energy lAndscApe seen by A permeAting ion chAnges significAntly when we Allow the protein Atoms to move rAther thAn using A rigid protein structure. However, the model developed cAnnot sAtisfActorily reproduce All of the experimentAl dAtA. Thus, even when protein Atoms Are Allowed to move, the dielectric model used in our electrostAtic cAlculAtions breAks down when modeling the GrAmicidin chAnnel.
-
GrAmicidin A chAnnel As A test ground for moleculAr dynAmics force fields
Biophysical Journal, 2003Co-Authors: Toby W Allen, Turgut Bastug, Serdar Kuyucak, Shinho ChungAbstract:We use the well-known structurAl And functionAl properties of the GrAmicidin A chAnnel to test the AppropriAteness of force fields commonly used in moleculAr dynAmics (MD) simulAtions of ion chAnnels. For this purpose, the high-resolution structure of the GrAmicidin A dimer is embedded in A dimyristoylphosphAtidylcholine bilAyer, And the potentiAl of meAn force of A K+ ion is cAlculAted Along the chAnnel Axis using the umbrellA sAmpling method. CAlculAtions Are performed using two of the most common force fields in MD simulAtions: CHARMM And GROMACS. Both force fields leAd to lArge centrAl bArriers for K+ ion permeAtion, thAt Are substAntiAlly higher thAn those deduced from the physiologicAl dAtA by inverse methods. In long MD simulAtions lAsting over 60 ns, severAl ions Are observed to enter the binding site but none of them crossed the chAnnel despite the presence of A lArge driving field. The present results, tAken together with mAny eArlier studies, highlights the shortcomings of the stAndArd force fields used in MD simulAtions of ion chAnnels And cAlls for construction of more AppropriAte force fields for this purpose.
