Molecular Dynamics Simulations of Salicylate Effects on the Micro- and Mesoscopic Properties of a Dipalmitoylphosphatidylcholine Bilayer

Abstract

Salicylate, an amphiphilic molecule and a popular member of non-steroidal antiinflammatory drug family, is known to affect hearing through reduction of the electromechanical coupling in the outer hair cells of the ear. This reduction of electromotility by salicylate has been widely studied but the molecular mechanism of the phenomenon is still unknown. In this study, we investigated one aspect of salicylate's action; namely, the perturbation of electrical and mechanical membrane properties by salicylate in the absence of cytoskeletal or membrane-bound motor proteins such as prestin. In particular, we simulated the interaction of salicylate with a dipalmitoylphosphatidylcholine (DPPC) bilayer via atomically-detailed molecular dynamics simulations to observe the effect of salicylate on the microscopic and mesoscopic properties of the bilayer. The results demonstrate that salicylate interacts with the bilayer by associating at the water-DPPC interface in a nearly perpendicular orientation and penetrating more deeply into the bilayer than either sodium or chloride. This association has several affects on the membrane properties. First, binding of salicylate to the membrane displaces chloride from the bilayer-water interface. Second, salicylate influences the electrostatic potential and dielectric properties of the bilayer, with significant changes at the waterlipid bilayer interface. Third, salicylate association results in structural changes including decreased head group area per lipid and increased lipid tail order. However, salicylate does not significantly alter the mechanical properties of the DPPC bilayer; bulk compressibility, area compressibility, and bending modulus were only perturbed by small, statistically-insignificant amounts, by the presence of salicylate. The observations from these simulations are in qualitative agreement with experimental data and support the conclusion that salicylate influences the electrical but not the mechanical properties of DPPC membranes. † This work was supported by NIH grant R01 GM069702 (NAB and YS) and an Alfred P. Sloan Research Fellowship (NAB).* To whom correspondence should be addressed. Dept. of Biochemistry and Molecular Biophysics, Center for Computational Biology, Washington Univ. St. Louis. 700 S. Euclid Ave., Campus Box 8036, St. Louis, MO 63110. Phone: (314) 362-2040, Fax: (314) 362-0234, E-mail: baker@biochem.wustl.edu, Web: http://agave.wustl.edu/. 1 Abbreviations: constant number-pressure-temperature (NpT), constant number-volume-temperature (NVT), dipalmitoylphosphatidylcholine (DPPC), giant unilamellar vesicle (GUV), human embryonic kidney (HEK), molecular dynamics (MD), outer hair cell (OHC), particle-mesh Ewald (PME), quantum mechanical/molecular mechanical (QM/MM), root mean squared (RMS), salicylate (SAL), solvent-accessible surface area (SASA), stearoyl-oleoylphosphatidylcholine (SOPC) Supporting Information Available Additional data, including figures of the QM/MM setup, time courses for system area, volume, and potential energy, select...

Effect of acetylsalicylic acid on the current–voltage characteristics of planar lipid membranes

“…They found that SA significantly decreased the area per head group of lipid molecules and increased the tail order of lipid bilayer. The most important is that salicylate significantly increased the electrostatic potential at the water-lipid interface and significantly affected dipole moment fluctuations of the bilayer molecules [38]. All these findings are in support of our present findings, as they can explain both the increased resistance of the voltage, these metastable single pores may become stabilized and form great pores (single ion channels) [32], thus providing a potential possibility of perpetuated diffusion of acetylsalicylic acid through the bilayer.…”

“…Song et al [38] studied the salicylate effects on the dipalmitoylphosphatidylcholine bilayer by molecular dynamics. They found that SA significantly decreased the area per head group of lipid molecules and increased the tail order of lipid bilayer.…”

Voltage-dependent capacitance of human embryonic kidney cells

“…Addition of salicylate to the external medium reduces the ψ s to about −0.023(±0.009) V. This suggests that salicylate adsorbs into the membrane decreasing the intrinsic charge asymmetry of the membrane. This is reasonable as there is much evidence to show that salicylate adsorbs into surfactant [29] and lipid [30][31][32] assemblies and cell membranes [33] increasing the surface charge density of the membranes, i.e., making it more negative. Its solubility is enhanced, relative to other benzoates, because the carbonyl and hydroxy group can form an intramolecular hydrogen bond [31] which increases its hydrophobic character and helps to drive its penetration into the membrane.…”

“…Its solubility is enhanced, relative to other benzoates, because the carbonyl and hydroxy group can form an intramolecular hydrogen bond [31] which increases its hydrophobic character and helps to drive its penetration into the membrane. Indeed, recent molecular dynamics simulations of a lipid bilayer shows that salicylate penetrates more deeply than chloride, displacing it from the water-bilayer interface [32]. This reduction in the charge asymmetry of the membrane by adsorption of salicylate was also suggested in an atomic force microscopy (AFM) study of the HEK cell [34].…”

A Quantitative Coarse-Grain Model for Lipid Bilayers

“…The choice of a 2 fs time step in the AL run is typical for AL membrane simulations. 19,[26][27][28][29][30][31][32][34][35][36] We are aware that the use of constraint and multistep algorithms can allow time steps of 4 21,22 and even 5 fs, 20,23 hence more than twice larger than that employed in our test. Using a 5 fs time step in the AL run would bring the CG speed-up factor down to ≈50.…”