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

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 transmembrane free energy landscapes of H2S and its structural analogue, water (H2O), seeking to decipher the molecular determinants that govern their drastically different permeabilities. Here, 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, that is, the interface between the polar head-group and nonpolar acyl chain regions. Because the membrane binding affinity of H2S is mainly governed by its small hydrophobic moiety and the barrier height inbetween the interfacial region and the membrane center is largely determined by its moderate polarity, the transmembrane 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. Lastly, this study not only explains why H2S can quickly pass through cell membranesmore » but also provides a practical illustration on how to use the OST free energy sampling method to conveniently analyze complex molecular processes.« less
 [1] ;  [2] ;  [3] ;  [2] ;  [4] ;  [5]
  1. Florida State Univ., Tallahassee, FL (United States). Dept. of Chemistry & Biochemistry
  2. Florida State Univ., Tallahassee, FL (United States). Inst. of Molecular Biophysics
  3. Institute of Molecular Biophysics, Florida State University, Tallahassee Florida 32306
  4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). UT-ORNL Center for Molecular Biophysics; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry, Cellular and Molecular Biology
  5. Florida State Univ., Tallahassee, FL (United States). Dept. of Chemistry & Biochemistry; Florida State Univ., Tallahassee, FL (United States). Inst. of Molecular Biophysics
Publication Date:
OSTI Identifier:
Grant/Contract Number:
AC05-00OR22725; MCB1158284
Accepted Manuscript
Journal Name:
Journal of Computational Chemistry
Additional Journal Information:
Journal Volume: 37; Journal Issue: 6; Journal ID: ISSN 0192-8651
Research Org:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Org:
ME USDOE - Office of Management, Budget, and Evaluation; ORNL work for others; National Science Foundation (NSF)
Country of Publication:
United States
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY free energy calculation; enhanced sampling; membrane permeation