What is hydrophobic interaction?

INTERACTION OF HYDROPHOBIC
MOLECULES IN AN AQUEOUS
ENVIRONMENT


Full text avaiable: Analysis of Electrostatic Interactions of Amino Acid Residues by the Example of Formation of a Nap1–Nap1 Dimer


Specific properties of water determine the behavior of dissolved molecules. The presence of a hydrogen bond network plays an important role in this case. It should be noted that water forms a very mobile net-work in the liquid state, in which hydrogen bonds always switch from one molecule to another.

Tendency of water molecules to form optimal network results in hydrophobic interaction phenomenon, which is interpreted as the force pulling molecules to each other.

The nature of this force is different from Coulomb or van der Waals forces. This interaction is not direct and acts through the structural rearrangement of surrounding water and hydrogen bond network. Water tends to form an optimal hydrogen bond network, which considers the presence of hydrophobic molecules, which results in their approach and thus cluster and clathrate structure formation.

Let us consider this process in detail.

We assume that positive values of potential energy of paired electrostatic interaction between hydrophobic amino acid residues indicate a repelling nature at small distances (in our case). However, when they are located in aqueous environment, which is characterized by the highdegree of ordered interaction between water molecules, hydrophobic clusters are formed. It should be noted that water molecules tend to
have a strong interaction between each other due to nonuniform distribution of electron density between an oxygen atom and two hydrogen atoms.

The character of formation of water molecules is that the electron density around an oxygen atom is much higher than that near hydrogen atoms, which in turn results in dipole formation, the ends of which carry unlike charge signs. The presence of such a dipole in a water molecule results in strong interaction with another dipole of water molecules; the environment of an oxygen atom carries a negative charge, while a hydrogen atom environment carries a positive charge. As a result, the oxygen atom of one molecule attracts the hydrogen atom of another water molecule forming a highly ordered structure of water molecule dipoles. We assume that hydrophobic molecules, which are not characterized by strong dipole–dipole interactions and are intrinsic for dispersion interactions, would distort the ordered structure of water dipoles.

Dispersion interaction

It should be noted that dispersion interactions arise between atoms due to fluctuations of electron density around the nucleus, which results in the appearance of an instant dipole moment at atoms and interaction of corresponding dipoles.

Dispersion interaction takes place between any atom groups; however, it is higher, when the polarizability of atoms is higher. In addition, dispersion forces play an important role in proteins during interaction of amino acid residues possessing hydrophobic (nonpolar) side radicals, such as valine, leucine, tryptophan, phenylalanine, and tyrosine.

The energy of dispersion interactions is inversely proportional to the sixth power of the distance between interacting atoms.

This implies that dispersion forces play a significant role only at short distances.

The behavior of hydrophobic molecules in an aqueous environment, indicating the effective forces, Frep is the electrostatic force
 interactions, Fsqz - force of compression (squeezing).
Fig.1-2.The behavior of hydrophobic molecules in an aqueous environment, indicating the effective forces, Frep is the electrostatic force
interactions, Fsqz — force of compression (squeezing).

Water molecules tend to have strong interactions and “pull” hydrophobic molecules to occupy the minimum volume in a water environment along the entire contact volume so that they would not prevent the formation of ordered structure of water dipoles. Thus, compression force (squeezing) acts on hydrophobic molecules in a water environment during ordering, which provides the formation of conglomerates from hydrophobic molecules; on the contrary, their structures (between hydrophobic molecules) are influenced by electrostatic interaction (with a positive sign magnitude), which results in repulsion of hydrophobic molecules from each other at small distances (Fig. 2). Because repulsion forces between atoms, which are related to repulsion of electron clouds during their interdigitation, manifest themselves.

This statement is rationalized by the fact that a molecule possesses both positive and negative charges, which are distributed nonhomogeneously by the molecule, as a result of which one side of the molecule is positively charged, while the other side is negatively charged. In addition, a significant fraction of the negative charge is distributed along the “external” electron shell, while the positive charge is located in nuclei of the atoms in molecules. Firstly, this results in the fact that molecules face each other with oppositely charged sides (plus to minus). Then, due to the fact that the electric field is nonuniform around the charge and possesses a gradient, that is, decays over a distance (proportionally to the square distance), it appears at relatively large distances that the attraction force between oppositely charged parts facing each other is marginally higher than the repulsion force between like-charged sides (though charges are identical, the distances are different due to turn of orientation, as well as forces are different); however, when molecules approach each other and their electron shells are very close to each other (in our case), it appears that the repulsion force between likely charged electron shells exceeds the attraction between the nuclei of one molecule and electron shells of another and the molecules would repel at such distance.

In this case, the attraction forces from the dipoles of water molecules are significantly higher than repulsion forces between hydrophobic molecules

ANALYSIS OF THE INTERACTION
OF TWO PROTEINS ILLUSTRATED
BY THE FORMATION OF A NAP1–NAP1

A new method is presented that allows you to analyze the potential energy of electrostatic interactions of protein complexes with point substitutions of amino acid residues taking into account three-dimensionalncomplex structure by the example of the formation of the Nap1 – Nap1 dimer Potential maps were developed energy of electrostatic interaction of paired amino acid residues involved proteins. The analysis of interacting proteins taking into account the three-dimensional structure.

The constructed model allows to melt such changes in affinity and choice of amino acids lots, the composition of the polypeptide chains to increase affinity of the biological complex and increase binding selectivity. In addition, to each mutant pathogenic protein, we can choose a specific inhibitor, taking into attention changes in conformation and redistribution electrostatic potential.

Amino acid residues of two polypeptide chains of two Nap1 proteins, which were replaced by hydrophobic tryptophan, are underlined. With the replacement of amino acid residues (six charged amino acids and one hydrophilic amino acid) by hydrophobic amino acid residues, a significant predominance of potential energy of paired electrostatic interaction is observed in the positive range of “high” values (21st exponent). Such behavior of hydrophobic amino acid residues in a water environment can be interpreted as “forced attraction.” In this case, we suggest that the water environment “forces” hydrophobic amino acid resi-dues to approach each other

The structure of the homodimer Nap1 − Nap1 with an indication of  hydrophilic, hydrophilic, charged a.a. In fig.  marked amino acid residues facing the polypeptide sequence of the second protein, as can be seen from the figure, most amino acids  residues in this case are hydrophobic. The formation of the dimer is due to the connection the polypeptide chains of two proteins in the opposite direction. It also follows from the figure that the formation of the Nap1 − Nap1 dimer is carried out mainly  hydrophobic amino acid residues. Let us calculate the potential energy of the electrostatic interaction of the two proteins Nap1 and Nap1.
Fig.3. Structure of Nap1–Nap1 homodimer with indica-
tion of hydrophobic, hydrophilic, and charged amino
acids.

Analysis of the interaction of two proteins on the example of education
homodimer Nap1 − Nap1

The graph of the three-dimensional representation of the energy in pairs electrostatic interaction  taking into account  the nature of the interacting A.A., the height of the bar corresponds  value of energy. In fig.  shows a map of the potential energy of electrostatic interaction, where we see different color bars, the height of which will correspond to a specific value of the energy that was calculated between each pair of amino acid residues of two polypeptide chains. On the graph, diagonal peaks (disturbances) are observed. The resulting graphical representation allowed us to analyze the effect of point substitutions of amino acid residues in protein polypeptide chains
Fig.4. 3D graph of the energy of paired electrostatic inter-
action (EPEI) with assumption of the nature of interacting
amino acids; the bar height corresponds to the magnitude
of EPEI of amino acid.

FORMATION OF A HYDROPHOBIC CLUSTER DUE TO SEVERAL REPLACEMENTS OF AMINO ACIDS IN PROTEINS: E110W, K111W, E112W, AND E116W OF ONE NAP1 PROTEIN AND E121W, N122W, AND Q126W OF ANOTHER NAP1 PROTEIN

Figure 5a shows the graphical representation of the matrix of potential energy of interaction from 82 to 120 amino acids of wild-type Nap1–Nap1 protein. Figure 5b shows the formation of a Nap1–Nap1 protein upon replacement of E110, K111, E112, and E116 amino acid residues of the one Nap1 protein and E121, N122, and Q126 of another Nap1 protein by hydrophobic tryptophan (W).

The formation of a hydrophobic cluster due to several replacements of amino acids in proteins:

Three-dimensional representation of potential energy   pairwise electrostatic interaction of two proteins  Nap1 and Nap1 in the formation of a homodimer in the case of proteins  wild type and in the case of the formation of a hydrophobic cluster.  The height of the bar corresponds to the value of potential energy  electrostatic interaction. As can be seen from the above figure. 5, the presence of a hydrophobic cluster led to a more uniform distribution of the potential interaction energy in positive values compared to the interaction of wild-type (wt) proteins.
Fig.5. 3D graph of the energy of paired electrostatic inter-
action (EPEI) of two Nap1 and Nap1 proteins during
homodimer formation in the case of wild-type proteins
and in the case of hydrophobic cluster formation. The bar
height corresponds to the magnitude of potential energy of
paired electrostatic interaction.

Electrostatic interaction energy, J

Replacement of hydrophilic a.a. T101A per hydrophobic amino acid residue

During the interaction of wild-type Nap1–Nap1 proteins, T101 (threonine 101) is characterized by a sufficiently high negative value of potential energy with K152 as compared to interactions of other amino acids; thus, hydrophilic threonine was replaced by hydrophobic alanine (A) and the potential energy of electrostatic interaction for such a replacement was recalculated. Let us present the part of the matrix in the range of key amino acid residues of two interacting proteins before and after replacement of T101A. As follows from Table 2, with the replacement of
T101A, there was an increase in the magnitude of potential energy of interaction. The values of potential energy in the positive range of values corresponding to the interaction of hydrophobic amino acids also appeared, which is considered as “attraction” in aqueous medium.

Figure 6 shows the region of two polypeptide chains of Nap1 and Nap1 proteins with indication of key amino acids, as well as indication of the change of potential energy of electrostatic interaction before and after replacement of T101A.

Replacement of hydrophilic A.A. T101A  per hydrophobic amino acid residue
Fig.6. Section of polypeptide chains of Nap1 and Nap1
proteins with indication of key amino acids during replace-
ment of T101A, as well as with the indication of the change
of potential energy of electrostatic interaction before and
after replacement.

Electrostatic interaction energy,J



It should be noted that it became possible to quantitatively evaluate the hydrophobic effect on the basis of the developed model through computer simulation and calculate the potential energy of paired electrostatic interaction between each pair of hydrophobic amino acid residues of two polypeptide chains of proteins assuming conformation.

Additional information

Three-dimensional representation of the energy interaction of two proteins Nap1 and Nap1
Fig.7. Three-dimensional representation of the energy interaction of two proteins Nap1 and Nap1

In this case, a dimer is formed by binding of two proteins in the opposite direction. The graph indicates the ordinal measurements of amino acid residues, while the countdown is from the 82nd amino acid residue of one protein Nap1 and the 83rd amino acid residue of Nap2, according to the database PDB: 5G2E


Table of values of potential energies of electrostatic interactions with several substitutions of amino acid residues with proline
Table of values of potential energies of electrostatic interactions with several substitutions of amino acid residues with proline

 Table of values of potential energies of electrostatic interactions with substitution  of amino acid residues with alanine
Table of values of potential energies of electrostatic interactions with substitution of amino acid residues with alanine

Three-dimensional map of potential energy of electrostatic interaction when replacing 101АЛА  in first NAP1
Fig.8. Three-dimensional map of potential energy of electrostatic interaction when replacing 101АЛА in first NAP1

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