Cleavage mechanism of the H5N1 hemagglutinin by trypsin and furin

Abstract

The cleavage property of hemagglutinin (HA) by different proteases was the prime determinant for influenza A virus pathogenicity. In order to understand the cleavage mechanism, molecular modeling tools were utilized to study the coupled model systems of the proteases, i.e., trypsin and furin and peptides of the cleavage sites specific to H5N1 and H1 HAs, which constitute models of HA precursor in complex with cleavage proteases. The peptide segments 'RERRRKKR downward arrow G' and 'SIQSR downward arrow G' from the high pathogenic H5N1 H5 and the low pathogenic H1N1 H1 cleavage sites were docking to the trypsin and furin active pockets, respectively. It was observed through the docking studies that trypsin was able to recognize and cleave both the high pathogenic and low pathogenic hemagglutinin, while furin could only cleave the high pathogenic hemagglutinin. An analysis of binding energies indicated that furin got most of its selectivity due to the interactions with P(1), P(4), and P(6), while having less interaction with P(2) and little interactions with P(3), P(5), P(7), and P(8). Some mutations of H5N1 H5 cleavage sequence fitted less well into furin and would reduce high pathogenicity of the virus. These findings hint that we should focus at the subsites P(1), P(4), and P(6) for developing drugs against H5N1 viruses.

Determination of inter- and intra-subtype/species varia-tions in polymerase acidic protein from influenza A virus using amino-acid pair predictability

“…Currently, the manufactured vaccines are designed to target the influenza A virus according to their subtypes, for example, the focus in recent year would be the H5N1 subtype of influenza A virus [7,8,9,10,11,12,13,14], and anti-flu drugs are designed to target neuraminidases and M2 protein [15,16]. It would be understandable that proteins should be different from one subtype to another.…”

Pathogenicity characterization with implicit and explicit molecular dynamics simulation

“…In the explicit solvation systems, complex molecules calculated without any implicit solvation energetic contribution while in the implicit solvation, the calculation executed with the addition of GBMV implicit solvation energy. The NA-SA complexes in HPAI is lower than LPAI for both solvation which in other way tells that the HPAI NA have a better interaction with SA than in the LPAI [27,28]. The similarity of the results could be seen as the indicator that pathogenicity characterization is available to perform either with implicit solvation or explicit solvation.…”

The Comparison of Substrate Stability in Neuraminidase Type 2 (N2) Active Site between A/Tokyo/3/67 and A/Pennsylvania/10218/84 with Heating Dynamics Simulation

“…The resulting values indicate that ligand binding is more favorable in Structure A than in Structure B [18,19]. Figure 3 depicts the overall movement of the sialic acid in response to the hydrogen bonds that form between the sialic acid and neuraminidase and the long range interactions in the 14 Å spherical cutoff range.…”