Protein, protein complexes. Analysis, modeling and drug design

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Protein‐Protein Interaction Modeling and Inhibition: The TAU Bioinfo3D Perspective

In the last decades, the incidence of Dengue disease has dramatically increased around the world. About 2. Every year, dengue virus DENV infects more than 50 million people, with approximately 22 fatal cases [ 23 ]. The disease is endemic in more than countries of Africa, America, Oriental Mediterranean, Southeast Asia, and the Western Pacific Ocean with the last two regions being the most affected by the disease.

Before only nine countries suffered from the Hemorrhagic Dengue HD epidemics, number that in was multiplied for more than four. There are four antigenically distinct, but closely related, serotypes of dengue virus DENV , which is a Flavivirus member of the family Flaviviridae [ 24 ]. Each serotype has genotypes, which are virulent at several levels; nevertheless, the factors of virulence are not totally established [ 25 ]. A better understanding of the mechanisms and the molecules involved in the key steps of the DENV transmission cycle may lead to the identification of new anti-dengue targets [ 26 ].

As a result, the diagnosis and treatment of dengue disease has become a world-wide global problem to deal with. While the glycosylation site at position is conserved in most flaviviruses, the site at position 67 is thought to be unique for dengue virus. N-linked oligosaccharide side chains on flavivirus E proteins have been associated with viral morphogenesis, infectivity, and tropism [ 27 , 28 ]. In addition, E protein is closely associated with the lipid envelope containing a cellular receptor-binding site s and a fusion peptide [ 29 ].

It can be found in a form of a homodimer on the surface of the mature virion, and inside the cell, it creates a prM-E heterodimer together with the prM protein. E protein is the principal component of the virion surface, containing the antigenic determinants epitopes responsible for the neutralization of the virus and the hemagglutination of erythrocytes, inducing thereby an immunological response in the infected host [ 29 ]. On native virions, the elongated three-domain E molecule is positioned tangentially to the virus envelope in a head-to-tail homodimeric conformation.

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Upon penetration of the virion into the target cell endosome, E dimers are converted into stable target-cell membrane-inserted homotrimers that reorient themselves vertically to promote virus-cell fusion at low pH [ 30 ]. Furthermore, there is a great deal of evidence that E protein contains the majority of molecular markers for pathogenicity.

Comparing the nucleotide sequence of the E protein gene in different flaviviruses has demonstrated a perfect conservation of 12 cysteine residues, which form six disulfide bridges. The structural model for the E protein was refined by Mandl and co-workers [ 31 ], who correlated the structural properties of different epitopes with disulfide bonds [ 32 ]. Given their structure, these polymers have specific molecular anchor sites that are expected to be exploited to induce antigenic specificity to the conserved regions of dengue virus.

Several authors report that the E protein produces immunity and confers protection against infection in mice with low levels of neutralizing antibodies [ 33 - 35 ]. Because of the dual role of its receptors as well as the cell entry through membrane fusion, the E protein, apart from being the most exposed protein, is the main target against which the neutralizing antibodies are produced to inhibit its functions. At present, the biggest challenge in developing an efficient dengue vaccine is to achieve a life-long protective immune response to all 4 serotypes DEN simultaneously.

Although several vaccines are currently being developed, so far only a chimeric dengue vaccine for live attenuated yellow fever YF has reached stage 3 in clinical trials.

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It is produced by deacetylation of chitin, which is extracted from the shells of crabs and shrimp. It is a linear, hydrophilic, positively charged, water soluble biopolymer, can form thin films, hydrogels, porous scaffolds, fibers, and micro and nanoparticles in mild acidity conditions. As a polycationic polymer, it has a high affinity to associate macromolecules such as insulin, pDNA, siRNA, heparin, among others, with antigenic molecules, protecting them in turn from hydrolytic and enzymatic degradation [ 37 ].

Polyvinylpyrrolidone N-vinylpyrrolidone, PVP has chemical, physical and physiological properties which have been exploited in various industries, including but not limited to medical, pharmaceutical, cosmetic, food, and textile, due to its biological compatibility, low toxicity, tackiness, resistance to thermal degradation in solutions as well as inert behavior in salt and acidic solutions [ 38 , 39 ]. It is a water soluble homopolymer with a wide range of molecular weights 2. When heated with strong bases such as lithium carbonate, trisodium phosphate or sodium metasilicate, it generates a precipitate due to the ring opening and subsequent crosslinking of chains.

Yen-Jen et al. In this work, the molecular docking calculations were performed using the AutoDock program. In particular, it uses a Lamarckian genetic algorithm LGA and a force field function based approximately on the AMBER force field, which consists of five terms: 1 the dispersion term of Lennard-Jones, 2 a directional hydrogen bonding term, 3 an electrostatic Coulomb potential, 4 an entropic term, and 5 one term of desolvation pairs.

The scaling factor of these terms is empirically calibrated using a set of 30 structurally-known protein-ligand complexes, which affinities have been experimentally determined. The AutoDock program has become widely used due to its good precision and high versatility; moreover, the latest version of AutoDock version 4. In this study we used the E protein of dengue virus. It consists of a dimer with amino acids aa per monomer and, as mentioned before, it is the main component of the dengue virus envelope.

E protein enters the cell by fusion with the membrane due to a previous conformational change produced by a low pH, generating thereby a change of form from dimer to trimer, in which the fusion peptide between the II and III domains is exposed.

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When the pH is lower than 6. Domain III then rotates backwards to pull the I and II domains, which were already bound to the cell membrane by the fusion peptide, thus attaching the cell membrane with the membrane of the virus in order to release the RNA [ 27 , 29 , 41 - 45 ]. It is important to mention that Bressanelli showed that the virus domains remain at neutral pH but their relative orientation is altered [ 27 ]. For best results during the molecular docking process, we optimize the original model of the dengue virus protein E PDB code 1OKE with a number of refinements and validations cycles with Phenix and Molprobity programs respectively.

Figure 3 shows the corrected model of the dimer and trimer.

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Dengue virus protein E. A Dimeric protein after geometric and refining corrections with Phenix program. B Trimeric protein that represents a postfusion state C Top view of the trimeric form. Domain I aa,, is in red, domain II aa, in yellow and domain III aa in blue color. Molecular docking was performed by means of the AutoDock program that combines rapid grid-based energy evaluation and efficient search of torsional freedom.

This program uses a semi-empirical free energy force field to evaluate the conformations during the docking simulations. The force field is quantified using a large number of protein-inhibitor complexes, for which the inhibition constants K i , are known. The force field evaluates the union in two steps, first when the ligand and the protein are separated. Then, the intramolecular energies are estimated for the transition from the unbound state to the protein-ligand bound state. In the second step, intermolecular energies are evaluated by combining the ligand with the protein conformations bound to themselves.

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The calculations can be summarized in the following four steps: 1 preparation of files using AutoDockTools coordinates, 2 pre-calculation of atomic affinities by using AutoGrid, 3 docking of ligands by using AutoDock, and 4 analysis of the results applying AutoDockTools. These amino acids are of particular interest since they are allocated in between I and II domains, the fusion loop of the host cell located between domains II and III, and aa kl loop. Also are important, the loop of fusion to the host cell located between domains II and III, which subsequently is exposed in the trimer with the aa fusion peptide, and the C-terminal of domain III, which holds the protein to the virus membrane.

Other important amino acids were mentioned by Mazumder [ 48 ], who made a structural analysis of the dengue virus E protein of the 4 serotypes in order to find the conserved and exposed sites as well as the epitopes in the T-cell. In our study, we additionally considered the sites of interest described by Yorgo Modis [ 42 , 43 ] Table 1.

In addition to the ten conserved regions presented in Table 1 , we predicted around E proteins of the 4 serotypes, some of which are included in the same Table 1. Their sequences were quantified using Shannon's entropy [ 48 ] with a variation from 0. Sites of interest identified in the structure of the dengue virus E protein according to Yorgo Modis [ 42 , 43 , 48 ].


The importance of this discovery relies on the fact that it has demonstrated that the epitopes with negative sites work better as vaccines than those with positive sites as they are less likely to change due to their functional restrictions. The docking of PVP molecules with the E protein of dengue virus has demonstrated that the interface of the I and II domain was the most energetically favorable site for the binding Figure 5.

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The interaction between protein and ligand takes place by establishing 8 hydrogen bonds with the Asn, Lys, and Asp amino acids Table 2. This region is extremely important for the pivotal role it plays in the conformational changes triggered by low pH, which in turn is closely related to the infectivity of the virus. In particular, the PVP molecule, which interacts with aa,, in the E protein-BOG ligand complex, could act as a blocker of the kl aa pitchfork activity, which is responsible for the conformational changes in the E protein at low pH. In other words, it could inhibit their function to work as a hinge for conformational changes due to its proximity to amino acids through steric hindrance, preventing thereby the hinge action between the I and II domain, which in turn could stiffen the area.

Alternatively, if BOG ligand is absent, the molecule could be internalized into the hydrophobic pocket and replace it, but the subsequent molecular prediction simulations would be required to determine how it could act in the presence of low pH, in order to find out whether the conformational changes would appear or be inhibited.

The PVP is well-known to be highly stable at acid pH and high temperatures, so its structural integrity is assured to remain intact; the loop or kl pitchfork amino acids mutate, resulting in an increase of the pH threshold, at which conformational changes occur. It is achieved by replacing long hydrophobic side chains by the short ones. As the result, the site can be consistently represented as a potential trigger in the virus replication cycle and a good candidate to inhibit its function Figure 5.

The docking of CS molecules in the E protein of dengue virus resulted in the interaction with the interface of domain I and II of the protein see Figure 6.

Computational methods in drug discovery

The CS ligand binds to seven amino acids of E protein by ten hydrogen bonds see Table 3. The elongated CS molecule settles into a channel formed in the II domain surface of the protein. Additionally, it interacts with amino acids near the kl hinge or loop of I and II domain interface. Amino acids-CS molecule interactions, which are shown in Table 10 aa65,68,,,,, , suggest that the mechanism of action of this molecule is similar to PVP ligand.

Additionally, it is very close to the conserved region VH that forms a channel in the 4 serotypes.

Protein, protein complexes. Analysis, modeling and drug design Protein, protein complexes. Analysis, modeling and drug design
Protein, protein complexes. Analysis, modeling and drug design Protein, protein complexes. Analysis, modeling and drug design
Protein, protein complexes. Analysis, modeling and drug design Protein, protein complexes. Analysis, modeling and drug design
Protein, protein complexes. Analysis, modeling and drug design Protein, protein complexes. Analysis, modeling and drug design
Protein, protein complexes. Analysis, modeling and drug design Protein, protein complexes. Analysis, modeling and drug design
Protein, protein complexes. Analysis, modeling and drug design Protein, protein complexes. Analysis, modeling and drug design
Protein, protein complexes. Analysis, modeling and drug design Protein, protein complexes. Analysis, modeling and drug design
Protein, protein complexes. Analysis, modeling and drug design Protein, protein complexes. Analysis, modeling and drug design
Protein, protein complexes. Analysis, modeling and drug design

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