Method For The Determination Of Intra- And Intermolecular Interactions In Aqueous Solution

Abstract

The present invention relates to the determination of intra- or intermolecular interaction between molecules in aqueous solution, said method comprising the steps of: (a) determining the dehydration (ΔG dehydration ) of all atoms in the intermolecular interface, (b) adding the vacuum hydrogen bond energy (ε H -bond), and (c) further adding the change in the free enthalpy of the interacting partners upon their interaction. The obtained results can be used for the prediction if and to what extent two molecules of various origin fit to each other.

1 . A method for the determination of intra- or intermolecular interactions in an aqueous solution, said method comprising the steps of:
 (a) determining the dehydration (ΔG dehydration ) of all atoms in the intermolecular interface,   (b) adding the vacuum hydrogen bond energy (ε H -bond), and   (c) further adding the change in the free enthalpy of the interacting partners upon their interaction.   
     
     
         2 . The method according to  claim 1 , wherein the dehydration is quantified by:
 (a) the determined fraction of saturated H-bond functions within the water network (f sat ),   (b) the determined fraction of unsaturated H-bond functions within the water network (f unsat ),   (c) the determined hydrogen bond energies between water molecules in the water network (ε° wat . . . wat ), and   (d) in case of a polar function the determined hydrogen bond energy between the polar function and the water network (ε° pol . . . wat ).   
     
     
         3 . The method according to  claim 2 , wherein f sat  and f unsat  are defined in pure bulk water by the terms as listed under (a) and (b)
   ( a )  f   sat ( T )=(Δ H   Fusion   +c   p ( T− 273K)/(Δ H   Fusion   +ΔH   Evaporation   +c   p *(373K−273K)), and     ( b )  f   unsat ( T )=(Δ H   Evaporation   +c   p *(373K− T )/(Δ H   Fusion   +ΔH   Evaporation   +C   p *(373K−273K)),   under the prerequisite that f sat +f unsat =1,   and wherein
 (i) ΔH Fusion  means the Enthalpy of the fusion of ice; 
 (ii) ΔH Evaporation  means the Enthalpy of Evaporation of water; and 
 (iii) c P  means specific heat of water. 
   
     
     
         4 . The method according to  claim 2 , wherein in case of polar functions a relationship between the dehydration term and the hydrogen bond energy (ε° pol . . . wat ) involving f sat  is used. 
     
     
         5 . The method according to  claim 2 , wherein in case of polar functions the relationship ΔG dehydration   i ˜f sat ·ε i . . . wat  is valid. 
     
     
         6 . The method according to  claim 2 , wherein f sat  is within a range 0.75 to 0.90. 
     
     
         7 . The method according to  claim 2 , wherein f sat  is within a range of 0.82 to 0.88. 
     
     
         8 . The method according to  claim 2 , wherein f sat  is within a range of 0.84 to 0.87. 
     
     
         9 . Use of the method of  claim 1  for the calculation of molecular interactions between at least 2 molecules in an aqueous solution and wherein one of the molecules is a target molecule which is to be bound by at least one interacting molecule. 
     
     
         10 . The use according to  claim 9 , in which the target molecule is selected from the group consisting of: proteins, nucleic acid molecules, or lipids. 
     
     
         11 . The use according to  claim 9 , in which the target molecule is selected from the group consisting of:
 cell wall proteins, membrane bound proteins, water soluble proteins, cellular proteins, enzymatic proteins, regulatory proteins, ion channel proteins, carrier proteins, aquaporins, vacuolar proteins, golgi apparatus proteins, cytoskeleton proteins, DNA- or RNA-replication proteins, DNA- or RNA-recombination proteins, viral proteins, mitochondrial proteins, plastid proteins involved in the respiration and photorespiration apparatus, proteins belonging to the signal transduction pathway, receptors, G-proteins, senescence proteins, plant stress proteins (including abiotic and biotic plant stress proteins), HMG-proteins (high mobility group proteins), LMG-proteins (low mobility group proteins), terpenoid synthesis proteins, DNA-molecules, RNA-molecules, transcriptions factors, phospholipids, galactosylglycerides, glucocerebrosides, and sterols.   
     
     
         12 . The use according to  claim 9 , in which interacting molecule is selected from the group consisting of:
 proteins, enzyme inhibitors, agonists, antagonists, compounds (having a molecular weight<600) g/mol and fragments of the latter.   
     
     
         13 . The use according to  claim 9  for the virtual screening analysis of compound libraries. 
     
     
         14 . The use according to  claim 9  for the identification of at least one interacting molecule with affinity to its specific target molecule. 
     
     
         15 . The use according to  claim 9  for the identification and visualization of the interacting portions of the target molecule and its interacting molecule enabling the estimation and/or definition of the correct binding mode. 
     
     
         16 . The use according to  claim 9  for the identification of interacting parts of the target molecule and its interacting molecule enabling the prediction of the strength of the binding of the interacting to its target molecule. 
     
     
         17 . The use according to  claim 9  for the identification of the interacting parts of the target molecule and its interacting molecule enabling the identification of regions contributing either favorably or unfavorably to the binding of the interacting molecules to the specific target molecule. 
     
     
         18 . The use according to  claim 9 , in which the interface between the target molecule and its interacting molecule is defined by three-dimensional coordinates that are:
 (a) defined by experimental data obtained from protein crystallography methods, X-ray diffraction, or NMR, or   (b) obtained from computer based calculations by applying the means of docking, molecular dynamics (MD) or Monte Carlo (MC) simulations, or   (c) obtained by manual maneuvering of the interacting molecule inside its primary docking area of the target molecule.   
     
     
         19 . The method according to  claim 3 , wherein in case of polar functions a relationship between the dehydration term and the hydrogen bond energy (ε° pol . . . wat ) involving f sat  is used. 
     
     
         20 . The method according to  claim 3 , wherein in case of polar functions the relationship ΔG dehydration   i ˜f sat ·ε i . . . wat  is valid.