Method for the determination of intra- and intermolecular interactions in aqueous solution
View Patent ↗The present invention relates to the determination of intra- or intermolecular interaction between molecules in aqueous solution, the method comprising the steps of: (a) determining the dehydration of all atoms in the intermolecular interface, (b) adding the vacuum hydrogen bond energy, 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 binding together at least two molecules, at least one target and at least one interacting molecule, so as to obtain a molecular complex, in an aqueous solution wherein the at least one target molecule is in a first library and the at least one interacting molecule is in a second library, said method comprising the steps of
(I) determining an interaction of each combination of a molecule from the first library and a molecule from the second library using a sufficiently programmed computer by the following steps:
(a) determining a dehydration energy (ΔG dehydration ) of all atoms in an intermolecular interface between the target molecule and at least one interacting molecule, wherein the atoms are selected from the group consisting of atoms with a polar function and atoms with an apolar function,
(b) adding a vacuum hydrogen bond energy (ε H -bond) between all atoms in the intermolecular interface to the determined dehydration energy so as to produce a result (a)+(b), and
(c) adding to the result (a)+(b) a change in the free enthalpy of the target molecule interacting with the at least one molecule upon their interaction so as to obtain possible molecular interactions,
(II) identifying at least one interacting molecule that is capable of binding to the target molecule from the possible molecular interactions and
(III) pairing the identified interacting molecule, so that the target molecule is bound to the identified interacting molecule so as to obtain a molecular complex.
2. The method according to claim 1 , wherein for the atoms with a polar function the dehydration energy is calculated by the following formula:
Δ
G
dehydration
polar
=
-
f
sat
·
ɛ
pol
…
wat
0
+
1
2
f
sat
·
ɛ
wat
…
wat
0
wherein
f sat is the determined fraction of saturated H-bond functions within the water network,
f unsat is the determined fraction of unsaturated H-bond functions within the water network,
ε 0 wat . . . wat is the determined hydrogen bond energies between water molecules in the water network, and
ε 0 pol . . . wat is the determined hydrogen bond energy between the polar function and the water network.
3. The method according to claim 1 , wherein for the atom with an apolar function the dehydration energy is calculated by the following formula:
Δ
G
dehydration
apolar
=
+
1
2
·
ɛ
wat
…
wat
0
(
1
-
T
373
K
)
>
0
,
wherein ε 0 wat . . . wat is the determined hydrogen bond energies between water molecules in the water network.
4. 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):
f sat ( T )=(Δ H Fusion +c p ( T− 273K)/(Δ H Fusion +ΔH Evaporation +c p *(373K−273K)), and (a)
f unsat ( T )=(Δ H Evaporation +c p *(373K− T )/(Δ H Fusion +ΔH Evaporation +C p *(373K−273K)), (b)
with the proviso 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.
5. The method according to claim 2 , wherein for the calculation of the dehydration energy an approximate equality exists as follows:
ε pol . . . wat 0 ≈ε wat . . . wat 0 .
6. The method according to claim 2 , wherein the dehydration energy for polar functions is represented by the following formula
Δ
G
dehydration
i
≈
1
2
f
sat
·
ɛ
i
…
wat
.
7. The method according to claim 2 , wherein f sat is within a range 0.75 to 0.90.
8. The method according to claim 2 , wherein f sat is within a range of 0.82 to 0.88.
9. The method according to claim 2 , wherein f sat is within a range of 0.84 to 0.87.
10. The method according to claim 5 , in which the target molecule in the first library is selected from the group consisting of proteins, nucleic acid molecules, and lipids.
11. The method according to claim 5 , wherein the target molecule in the first library 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 method according to claim 5 , in which the interacting molecule in the second library is selected from the group consisting of: proteins, enzyme inhibitors, agonists, antagonists, small weight compounds (molecular weight <600 g/mol) and fragments of the latter.
13. The method according to claim 1 , in which the intermolecular 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.
14. The method according to claim 2 , wherein for the calculation of the dehydration energy an approximate equality exists as follows
ε pol . . . wat 0 ≈ε wat . . . wat 0 .
15. The method according to claim 4 , wherein the dehydration energy for polar functions is represented by the following formula
Δ
G
dehydration
i
≈
1
2
f
sat
·
ɛ
i
…
wat
.
16. The method according to claim 2 , wherein the target molecule in the first library is selected from the group consisting of proteins, nucleic acid molecules, and lipids.
17. The method according to claim 2 , wherein the interacting molecule in the second library is selected from the group consisting of: proteins, enzyme inhibitors, agonists, antagonists, small weight compounds (molecular weight <600 g/mol) and fragments of the latter.