Structure and stability of complexes of charged structural units of heparin with arginine and lysine

M. Remko, Piet Th. van Duijnen, Ria Broer

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Abstract

Our work reports in detail the results of systematic large-scale theoretical investigations of the complexes modeling heparin-protein interaction (CH3OSO3-center dot center dot center dot Arg(+), CH3NHSO3-center dot center dot center dot Arg(+), CH3CO2-center dot center dot center dot Arg(+), CH(3)OSO(3)(-)Lys(+), CH3NHSO3-center dot center dot center dot Lys(+), CH3CO2-center dot center dot center dot Lys(+), CH3OPO3H2-center dot center dot center dot Arg(+), CH3OPO3H2-center dot center dot center dot Lys(+), CH3O(CH3)PO2-center dot center dot center dot Arg(+), CH3O(CH3)PO2-center dot center dot center dot Lys(+), 1,4-DiOMeldoA2SNa(-)center dot center dot center dot Arg(+), 1,4-DiOMeldoA2SNa(-)center dot center dot center dot Lys(+)) using Becke3LYP and B97D levels of the density functional theory, as well as at MP2 ab initio method. Although initial geometries of complexes paired anionic and cationic species (ionic hydrogen bonds), full geometry optimization of isolated systems resulted in several cases with relaxed geometry and complexes stabilized via neutral hydrogen bonds. Hydration caused appreciable geometry changes, especially for substituents (carboxylate and sulphate groups) of the saccharidic part of the complex. The computed Gibbs energies Delta G degrees of the ionic hydrogen bond systems are negative and high (from -340 to -450 kJ mol(-1)) . In complexes with neutral H-bonds the large destabilizing effect of entropy drives the association reaction to the left. However, owing to a sufficient enthalpy change Gibbs energies are indeed negative, but small (from -20 to 0 kJ mol(-1)) and the tendency to associate in gas-phase for the complex CH3OPO3H-center dot center dot center dot Lys(+) is negligible. The phosphate anion in its complexes with arginine and lysine proved the lowest tendency to associate. Displacing of Na+ ions from heparine binding sites by protonated arginine and lysine molecules resulted in positive reaction energies. Solvent (water) reversed the reactivity. Reaction energies computed for the reactions conducted in water are calculated negative, i.e. water drives these reactions to the right.

Original languageEnglish
Pages (from-to)1789-1796
Number of pages8
JournalRSC Advances
Volume3
Issue number6
DOIs
Publication statusPublished - 2013

Keywords

  • GLYCOSAMINOGLYCAN-PROTEIN INTERACTIONS
  • CONTINUUM SOLVATION MODELS
  • DENSITY-FUNCTIONAL THEORY
  • ANTITHROMBIN-III
  • BINDING-PROTEINS
  • SULFATE
  • ENERGIES
  • EXCHANGE
  • PENTASACCHARIDE
  • THERMODYNAMICS

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