[46]

[46]. the enzymatic activity is usually qualitatively evident, which further validates our methodology, leading to the development of an accurate quantitative metric to predict protease activity where is the vector from O of S139 to N1 of H57 and is the vector from O of S139 to O2 of D81. The distribution of the area of the triangle was monitored during the course of the simulation. The residue-residue and backbone-backbone cross-correlations were calculated using the Linear Mutual Information [70C72] algorithm implemented in WORDAM. The energy calculations were done using the NAMD Energy plugin in VMD. RMSD and RMSF calculations were performed using VMDs measure function [73]. Results and Discussion The rigid backbone structures of HCV-1b and HCV-3a protease models are indistinguishable, with backbone RMSD around 0.2 ? (Fig 1A). The sequence identity between the two proteases is about 80% (Fig 1C). The conserved catalytic triad residues H57, D81, and S139 are positioned in a cleft between two -barrels (Fig 1A) [47, 74, 75], forming a non-polar and shallow active site [31]. The rigid structures show that this active sites in both models are equally accessible. The structures also indicate that the main region of NS4A (residues 21C34) is usually buried within the protease to function as a fold-aiding cofactor (Fig 1A) [75]. None of the 181 amino acids exhibit steric clashes or stereochemical outliers, and Molecular dynamics (MD) simulations predict that both HCV-1b and HCV-3a proteases equilibrate at an average RMSD in the C positions of about 2.5 ? (Fig 1B). Open in a separate windows Fig 1 Comparison between the 3D structural models and dynamics of HCV-3a and the HCV-1b NS3 protease.(a) Structural models of HCV-1b (green) and HCV-3a (magenta) are superimposed. The transparent box highlights the catalytic triad (H57, D81, and S139). (b) Residue-average RMSD of C atoms for the models of HCV-1b (green), HCV-3a (magenta) and HCV3a* (gold, see methods) during the simulation. (c) The alignment of the amino acid sequences of HCV-1b (green), HCV-3a (magenta) NS3 proteases, as well as their corresponding NS4A cofactors. Dots show identical sequences. However, 1-Azakenpaullone MD simulations locally exhibit a genotype-dependent, divergent dynamics profile within the catalytic triad region, with HCV-1b protease being the most stable and the HCV-3a the most deviating (Figs ?(Figs2,2, ?,33 and ?and4).4). These dynamic distinctions have a strong correlation with the alterations in catalytic activities (Fig 4B) and drug responsiveness to linear inhibitors observed in these two genotypes [19, 46]. 1-Azakenpaullone In this regard, this result implies that the triad regions intrinsic dynamics could directly predict HCV pan-genotype enzymatic 1-Azakenpaullone activities and its subsequent physiological/clinical ramifications, such as the ability of host cells to elicit an innate immune response and respond to interferon based therapy [46, 48]. Open in a separate windows Fig 2 Comparison of the dynamical behavior of the catalytic triad residues among the protease models (HCV-1b, green, HCV-3a, magenta, and HCV-3a*, gold).RMSD values for each catalytic residue are shown for the entire residue (a, c, e) and the corresponding C atom (b,d,f). Open in a separate windows Fig 3 Dynamical behavior within the catalytic triad region of the protease models (HCV-1b, green, HCV-3a, magenta, and HCV-3a*, gold).The distance distribution profiles (a) between O of residue S139 and N2 of residue H57, and (b) between O2 of residues D81 and N1 of H57, during the stimulation for the threading protease models (HCV-1b, green, HCV-3a, magenta and HCV-3a*, gold). Blue and cyan arrows indicate the selected distances in the rigid structures. Open in a separate windows Fig 4 The conjoint dynamical behavior of the catalytic triad site GPM6A expressed as the area of a triangle (yellow) whose vertices lie on each catalytic residue (a). (b) The 1-Azakenpaullone area distribution profile of the triangle bridging 1-Azakenpaullone the catalytic residues in the models (HCV-1b, green, HCV-3a, magenta and.

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