Brownian Dynamics Simulations of Ion Transport through the VDAC

This is the publisher's version. Copyright 2011 by Elsevier.It is important to gain a physical understanding of ion transport through the voltage-dependent anion channel (VDAC) because this channel provides primary permeation pathways for metabolites and electrolytes between the cytosol and mitochondria. We performed grand canonical Monte Carlo/Brownian dynamics (GCMC/BD) simulations to explore the ion transport properties of human VDAC isoform 1 (hVDAC1; PDB:2K4T) embedded in an implicit membrane. When the MD-derived, space-dependent diffusion constant was used in the GCMC/BD simulations, the current-voltage characteristics and ion number profiles inside the pore showed excellent agreement with those calculated from all-atom molecular-dynamics (MD) simulations, thereby validating the GCMC/BD approach. Of the 20 NMR models of hVDAC1 currently available, the third one (NMR03) best reproduces both experimental single-channel conductance and ion selectivity (i.e., the reversal potential). In addition, detailed analyses of the ion trajectories, one-dimensional multi-ion potential of mean force, and protein charge distribution reveal that electrostatic interactions play an important role in the channel structure and ion transport relationship. Finally, the GCMC/BD simulations of various mutants based on NMR03 show good agreement with experimental ion selectivity. The difference in ion selectivity between the wild-type and the mutants is the result of altered potential of mean force profiles that are dominated by the electrostatic interactions

Molecular Dynamics Studies of Ion Permeation in VDAC

This is the publisher's version. Copyright 2011 by Elsevier.The voltage-dependent anion channel (VDAC) in the outer membrane of mitochondria serves an essential role in the transport of metabolites and electrolytes between the cell matrix and mitochondria. To examine its structure, dynamics, and the mechanisms underlying its electrophysiological properties, we performed a total of 1.77 μs molecular dynamics simulations of human VDAC isoform 1 in DOPE/DOPC mixed bilayers in 1 M KCl solution with transmembrane potentials of 0, ±25, ±50, ±75, and ±100 mV. The calculated conductance and ion selectivity are in good agreement with the experimental measurements. In addition, ion density distributions inside the channel reveal possible pathways for different ion species. Based on these observations, a mechanism underlying the anion selectivity is proposed; both ion species are transported across the channel, but the rate for K+ is smaller than that for Cl− because of the attractive interactions between K+ and residues on the channel wall. This difference leads to the anion selectivity of VDAC

Assessing smectic liquid-crystal continuum models for elastic bilayer deformations

For four decades, since W. Helfrich’s pioneering study of smectic A liquid crystals in 1973, continuum elastic models (CEMs) have been employed as tools to understand the energetics of protein-induced lipid bilayer deformations. Among the assumptions underlying this use is that all relevant protein–lipid interactions can be included in the continuum representation of the protein–bilayer interactions through the physical parameters determined for protein-free bilayers and the choice of boundary conditions at the protein/bilayer interface. To better understand this assumption, we review the general structure of CEMs, examine how different choices of boundary conditions and physical moduli profiles alter the predicted bilayer thickness profiles around gramicidin A (gA) and mitochondrial voltage-dependent anion channels (VDAC), respectively, and compare these profiles with those obtained from all-atom molecular dynamics simulations. We find that the profiles differ qualitatively in the first lipid shell around the channels, indicating that the CEMs do not capture accurately the consequences of the protein-induced local changes in lipid bilayer dynamics. Therefore, one needs to be careful when interpreting the results of CEM-based analyses of lipid bilayer-membrane protein interactions

Influence of Hydrophobic Mismatch on Structures and Dynamics of Gramicidin A and Lipid Bilayers

This is the publisher's version. Copyright 2012 by Elsevier.Gramicidin A (gA) is a 15-amino-acid antibiotic peptide with an alternating L-D sequence, which forms (dimeric) bilayer-spanning, monovalent cation channels in biological membranes and synthetic bilayers. We performed molecular dynamics simulations of gA dimers and monomers in all-atom, explicit dilauroylphosphatidylcholine (DLPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), and 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayers. The variation in acyl chain length among these different phospholipids provides a way to alter gA-bilayer interactions by varying the bilayer hydrophobic thickness, and to determine the influence of hydrophobic mismatch on the structure and dynamics of both gA channels (and monomeric subunits) and the host bilayers. The simulations show that the channel structure varied little with changes in hydrophobic mismatch, and that the lipid bilayer adapts to the bilayer-spanning channel to minimize the exposure of hydrophobic residues. The bilayer thickness, however, did not vary monotonically as a function of radial distance from the channel. In all simulations, there was an initial decrease in thickness within 4–5 Å from the channel, which was followed by an increase in DOPC and POPC or a further decrease in DLPC and DMPC bilayers. The bilayer thickness varied little in the monomer simulations—except one of three independent simulations for DMPC and all three DLPC simulations, where the bilayer thinned to allow a single subunit to form a bilayer-spanning water-permeable pore. The radial dependence of local lipid area and bilayer compressibility is also nonmonotonic in the first shell around gA dimers due to gA-phospholipid interactions and the hydrophobic mismatch. Order parameters, acyl chain dynamics, and diffusion constants also differ between the lipids in the first shell and the bulk. The lipid behaviors in the first shell around gA dimers are more complex than predicted from a simple mismatch model, which has implications for understanding the energetics of membrane protein-lipid interactions

Influence of Hydrophobic Mismatch on Structures and Dynamics of Gramicidin A and Lipid Bilayers

This is the publisher's version. Copyright 2012 by Elsevier.Gramicidin A (gA) is a 15-amino-acid antibiotic peptide with an alternating L-D sequence, which forms (dimeric) bilayer-spanning, monovalent cation channels in biological membranes and synthetic bilayers. We performed molecular dynamics simulations of gA dimers and monomers in all-atom, explicit dilauroylphosphatidylcholine (DLPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), and 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayers. The variation in acyl chain length among these different phospholipids provides a way to alter gA-bilayer interactions by varying the bilayer hydrophobic thickness, and to determine the influence of hydrophobic mismatch on the structure and dynamics of both gA channels (and monomeric subunits) and the host bilayers. The simulations show that the channel structure varied little with changes in hydrophobic mismatch, and that the lipid bilayer adapts to the bilayer-spanning channel to minimize the exposure of hydrophobic residues. The bilayer thickness, however, did not vary monotonically as a function of radial distance from the channel. In all simulations, there was an initial decrease in thickness within 4–5 Å from the channel, which was followed by an increase in DOPC and POPC or a further decrease in DLPC and DMPC bilayers. The bilayer thickness varied little in the monomer simulations—except one of three independent simulations for DMPC and all three DLPC simulations, where the bilayer thinned to allow a single subunit to form a bilayer-spanning water-permeable pore. The radial dependence of local lipid area and bilayer compressibility is also nonmonotonic in the first shell around gA dimers due to gA-phospholipid interactions and the hydrophobic mismatch. Order parameters, acyl chain dynamics, and diffusion constants also differ between the lipids in the first shell and the bulk. The lipid behaviors in the first shell around gA dimers are more complex than predicted from a simple mismatch model, which has implications for understanding the energetics of membrane protein-lipid interactions

Web Interface for Brownian Dynamics Simulation of Ion Transport and Its Application to Beta-Barrel Pores

This is the peer reviewed version of the following article: Lee, K. I., Jo, S., Rui, H., Egwolf, B., Roux, B., Pastor, R. W., & Im, W. (2012). Web Interface for Brownian Dynamics Simulation of Ion Transport and Its Applications to Beta-Barrel Pores. Journal of Computational Chemistry, 33(3), 331–339. http://doi.org/10.1002/jcc.21952, which has been published in final form at http://doi.org/10.1002/jcc.21952. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Brownian dynamics (BD) in a suitably constructed potential of mean force is an efficient and accurate method for simulating ion transport through wide ion channels. Here, a web-based graphical user interface (GUI) is presented for grand canonical Monte Carlo (GCMC) BD simulations of channel proteins: http://www.charmm-gui.org/input/gcmcbd. The webserver is designed to help users avoid most of the technical difficulties and issues encountered in setting up and simulating complex pore systems. GCMC/BD simulation results for three proteins, the voltage dependent anion channel (VDAC), α-Hemolysin, and the protective antigen pore of the anthrax toxin (PA), are presented to illustrate system setup, input preparation, and typical output (conductance, ion density profile, ion selectivity, and ion asymmetry). Two models for the input diffusion constants for potassium and chloride ions in the pore are compared: scaling of the bulk diffusion constants by 0.5, as deduced from previous all-atom molecular dynamics simulations of VDAC; and a hydrodynamics based model (HD) of diffusion through a tube. The HD model yields excellent agreement with experimental conductances for VDAC and α-Hemolysin, while scaling bulk diffusion constants by 0.5 leads to underestimates of 10–20%. For PA, simulated ion conduction values overestimate experimental values by a factor of 1.5 to 7 (depending on His protonation state and the transmembrane potential), implying that the currently available computational model of this protein requires further structural refinement

Mixed Bino-Wino-Higgsino Dark Matter in Gauge Messenger Models

Almost degenerate bino and wino masses at the weak scale is one of unique features of gauge messenger models. The lightest neutralino is a mixture of bino, wino and higgsino and can produce the correct amount of the dark matter density if it is the lightest supersymmetric particle. Furthermore, as a result of squeezed spectrum of superpartners which is typical for gauge messenger models, various co-annihilation and resonance regions overlap and very often the correct amount of the neutralino relic density is generated as an interplay of several processes. This feature makes the explanation of the observed amount of the dark matter density much less sensitive to fundamental parameters. We calculate the neutralino relic density assuming thermal history and present both spin independent and spin dependent cross sections for the direct detection. We also discuss phenomenological constraints from b to s gamma and muon g-2 and compare results of gauge messenger models to well known results of the mSUGRA scenario.Comment: 27 pages, 9 figures, references added, version to appear at JCA

Intra-Arterial Thrombolysis after Full-Dose Intravenous tPA via the "Drip and Ship" Approach in Patients with Acute Ischemic Stroke: Preliminary Report

According to the "drip and ship" concept, patients who are not responsive to intravenous tissue plasminogen activator (IV-tPA) at a community hospital may be candidates for subsequent intra-arterial (IA) thrombolysis at a comprehensive stroke center. We elucidated the efficacy and safety of combined IV/IA thrombolysis via the drip and ship approach. We retrospectively reviewed patients with acute ischemic stroke who underwent combined IV/IA thrombolysis between March 2006 and June 2009. The patients were divided into two groups (inside hospital IV-tPA vs. outside hospital IV-tPA). We compared the short- and long-term clinical outcome, recanalization rate, intracranial hemorrhage after the procedure, and onset to treatment time between the two groups. A total of 23 patients with inside hospital IV-tPA and 10 patients with outside hospital IV-tPA were included. The mean pre-treatment National Institutes of Health Stroke Scale (NIHSS) scores were 15.8 and 17.5, respectively. Baseline characteristics were not significantly different between the two groups. The NIHSS score at 1 week and favorable outcome rate (modified Rankin Scale ≤2) 3 months after the procedure were not significantly different (p=0.730 and p=0.141, respectively). The rate of recanalization and intracranial hemorrhage were not significantly different (p=0.560 and p=0.730, respectively). The onset to IA thrombolysis time was also not significantly different (222.7 vs. 239.3 minutes, p=0.455). Our results suggest that initiation of IV-tPA in a community hospital with rapid transfer to a comprehensive stroke center for subsequent IA thrombolysis can be a safe and feasible therapeutic option in acute stroke management