Comparative exploration of hydrogen sulfide and water transmembrane free energy surfaces via orthogonal space tempering free energy sampling

Abstract

Hydrogen sulfide (H2S), a commonly known toxic gas compound, possesses unique chemical features that allow this small solute molecule to quickly diffuse through cell membranes. Taking advantage of the recent orthogonal space tempering (OST) method, we comparatively mapped the trans-membrane (POPC) free energy landscapes of H2S and its structural analogue, water (H2O), seeking to decipher the molecular determinants that govern their drastically different permeabilities. As revealed by our OST sampling results, in contrast to the highly polar water solute, hydrogen sulfide is evidently amphipathic, and thus inside membrane is favorably localized at the interfacial region, i.e. the interface between the polar head-group and non-polar acyl chain regions. Because the membrane binding affinity of H2S is mainly governed by its small hydrophobic moiety and the barrier height in between the interfacial region and the membrane center is largely determined by its moderate polarity, the trans-membrane free energy barriers to encounter by this toxic molecule are very small. Moreover when H2S diffuses from the bulk solution to the membrane center, the above two effects nearly cancel each other, so as to lead to a negligible free energy difference. This study not only explains why H2S can quickly pass through cell membranes but also provides a practical illustration on how to employ the OST free energy sampling method to conveniently analyze complex molecular processes.

Molecular Dynamics Simulations of the Silica–Cell Membrane Interaction: Insights on Biomineralization and Nanotoxicity

“…It remains mostly unchanged for the POPC_CH case, with just a moderate increase for the crossing of the erythrocyte RBC model membrane. These values compare well with a simulation recently reported in the literature (26.3 kJ mol –1 ) for water crossing a homogeneous POPC membrane, with a similar setup but employing a different free-energy estimation method (orthogonal space tempering) . These data are also in good agreement with the experimental water-to-hexadecane transfer free energy (24.9 kJ mol –1 , from the Minnesota Solvation Database).…”

An In Silico study of TiO2 nanoparticles interaction with twenty standard amino acids in aqueous solution

“…This technique was considered adequate for our purposes since there are no ‘slow structural responses’ along the defined pathway. Slow structural responses, such as those observed in the interactions in solute-membrane systems, exemplify cases where recent advanced methods provide a better description of the system39. The PMF was calculated along a reaction coordinate defined by pulling the capped amino acids toward the NP surface with a harmonic force of 2000 kJ mol −1 nm −2 applied on the heavy atoms of the side chain to bringing it from a distance of 2.6 nm to 1.8 nm (the radius of the NP was 1.7 nm); in some cases a larger harmonic force of 5000 kJ mol −1 nm −2 was applied on the heavy atoms at NP surface (1.8–2.0 nm) in order to improve samplings.…”

Accelerating potential of mean force calculations for lipid membrane permeation: System size, reaction coordinate, solute-solute distance, and cutoffs

“…In recent years, much work has been carried out for the development of better force fields for lipids [19][20][21][22][23][24][25][26] and small molecules, 27,28 as well as for improved sampling algorithms to allow for more accurate and more efficient permeation simulations. 8,9,17,18,29,30 In contrast, only few studies systematically analyzed simple methods for accelerating PMF calculations of membrane permeation, such as using smaller simulation systems, shorter cutoffs, 11 or simulating multiple solutes per simulation system, despite the fact that such parameters may be tuned with any MD software without methodological overhead.…”

“…1 Hence, in recent years much effort has been invested in the development of computational tools for accurate yet efficient predictions of membrane permeabilities and partition free energies between membranes and water. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] The permeability is mainly determined by the partitioning of the solute into the membrane, which can be quantified by the potential of mean force (PMF) for solute translocation over the membrane. PMFs for membrane permeation are often calculated using molecular dynamics (MD) simulations, which provide an accurate physical model of the membrane (Ref.…”