Molecular models of NS3 protease variants of the Hepatitis C virus

Abstract

BackgroundHepatitis C virus (HCV) currently infects approximately three percent of the world population. In view of the lack of vaccines against HCV, there is an urgent need for an efficient treatment of the disease by an effective antiviral drug. Rational drug design has not been the primary way for discovering major therapeutics. Nevertheless, there are reports of success in the development of inhibitor using a structure-based approach. One of the possible targets for drug development against HCV is the NS3 protease variants. Based on the three-dimensional structure of these variants we expect to identify new NS3 protease inhibitors. In order to speed up the modeling process all NS3 protease variant models were generated in a Beowulf cluster. The potential of the structural bioinformatics for development of new antiviral drugs is discussed.ResultsThe atomic coordinates of crystallographic structure 1CU1 and 1DY9 were used as starting model for modeling of the NS3 protease variant structures. The NS3 protease variant structures are composed of six subdomains, which occur in sequence along the polypeptide chain. The protease domain exhibits the dual beta-barrel fold that is common among members of the chymotrypsin serine protease family. The helicase domain contains two structurally related beta-alpha-beta subdomains and a third subdomain of seven helices and three short beta strands. The latter domain is usually referred to as the helicase alpha-helical subdomain. The rmsd value of bond lengths and bond angles, the average G-factor and Verify 3D values are presented for NS3 protease variant structures.ConclusionsThis project increases the certainty that homology modeling is an useful tool in structural biology and that it can be very valuable in annotating genome sequence information and contributing to structural and functional genomics from virus. The structural models will be used to guide future efforts in the structure-based drug design of a new generation of NS3 protease variants inhibitors. All models in the database are publicly accessible via our interactive website, providing us with large amount of structural models for use in protein-ligand docking analysis.

Conformational Relaxation and Water Penetration Coupled to Ionization of Internal Groups in Proteins

“…The standard programs for secondary structure assignment, such as DSSP 58 used in this study, use criteria based on hydrogen bond patterns. Others, such as STRIDE, 59 use a combination of hydrogen-bond patterns and phi/psi angles, and others, such as KAKSI, 60 use C α distances and phi/psi angles. Residues for which secondary structure assignment depends on the method used may often exhibit a partially unfolded secondary structure content.…”

Self‐guided Langevin dynamics study of regulatory interactions in NtrC

“…The largest loss, of about 9 % is for helix α 4. To determine whether this loss is real, and not simply an artifact of the way that DSSP assigns secondary structure (i.e., based on hydrogen-bond patterns), average secondary structure was also calculated with another method, kaksi [34] (based on C α distances and Φ/Ψ angles). The loss in secondary structure of helix α 4 determined with this method is 1 %, suggesting that the decay in secondary structure observed by DSSP does not involve large structural changes of the helix.…”

“…The maximal α -helical content of helix α 4 calculated with DSSP [33] is 77 % in simulations of ${\text{BeF}}_3^{-}-{\text{NtrC}}^r$, 92 % in simulations of ${\text{BeF}}_3^{-}-{\text{NtrC}}^r-\text{P}$, and 89 % in simulations of ${\text{BeF}}_3^{-}-{\text{NtrC}}^r-\text{P}-\text{Hsp}84$. With kaksi [34], the maximal α -helical content is 93% ${\text{BeF}}_3^{-}-{\text{NtrC}}^r$, 98% ${\text{BeF}}_3^{-}-{\text{NtrC}}^r-\text{P}$ and 97% for ${\text{normalBeF}}_3^{-}-\mathrm{\text{Ntr}}{\mathrm{normalC}}^r-\mathrm{P}-\mathrm{\text{Hsp}}84$. This is an indication that partial unfolding of helix α 4 is not simply a characteristic of the local structural ensemble, but a consequence of dephosphorylation.…”

Bioinformatic Identification of Rare Codon Clusters (RCCs) in HBV Genome and Evaluation of RCCs in Proteins Structure of Hepatitis B Virus

“…Analysis of the modeled L-protein from HBSAG-HHBV and DNA polymerase protein in PROCHECK showed that 96.1% and 95% of the residues are located in the favored region and 3.9% and 5% in disallow region of the Ramachandran plot, respectively (Figure 4). The reference set and resulting φ and ψ distributions are described in structure validation by Cα geometry: φ, ψ and Cβ deviation (43). …”