Indonesian avian influenza H274Y mutant neuraminidase homology models assessment

Five models of Indonesian H274Y mutant neuralminidase type 1 (N1) were generated from the template 3CKZ by homology modeling. The template has the best similarity percentage 97% with the model sequence. The models was evaluated to search the best model with DOPE, 3D-profiles and PROCHECK in a good rank. The results show model 3 as a potential model to be used in the simulation with the lowest DOPE score, highest verify-3D score and from Ramachandran plots we inferred that it also shared the 1st rank with model 4 based on the 99.4% of the residues found, without Glycine and Proline, at the most favoured and additionally allowed region of both model structures.

Molecular docking investigation for Indonesian H274Y mutant neuraminidase type 1 with neuraminidase inhibitors

The aim of this study is to get insight the interaction between Indonesian H274Y mutant neuraminidase with four inhibitors. Not only to seek preferable inhibitor to be used, but also to investigate the interaction occurred, especially hydrogen bonds formed. Hydrogen bonds analysis and its interaction energies calculation showed that zanamivir is the most preferable inhibitor with 13 hydrogen bonds formed and –439.96 kcal/mol. Laninamivir would be an alternative inhibitor since it has 10 hydrogen bonds and –307.19 kcal/mol. The investigation of ΔSAS showed almost all active site residues buried when interacted with inhibitors. Only a few residues have an increases ΔSAS. Lipinski rule analysis showed that zanamivir and laninamivir would be best taken by injection or inhalation.

Pathogenicity characterization with implicit and explicit molecular dynamics simulation

The contribution of water molecules in molecular dynamics simulation (MDS) is unquestionably high, particularly for enzymatic interaction which occurred in the cytoplasmic environment. The addition of water molecules to the system will surely influence different direct interaction between active site residues and substrate. We try to theoretically investigate to what extent the pathogenicity characterization will varies in different neuraminidase-sialic acid complex systems. The heating dynamics simulations were produced with and without TIP3P water molecules. The periodic boundary system was made for explicitly added TIP3P water molecules and generalized born molecular volume (GBMV) energy contribution was added for implicit solvent system. Both complexes, neuraminidasesialic acid of A/Tokyo/3/67 and A/Pennsylvania/10218/ 84, which have a different pathogenicity levels were minimized and simulated. The result shows more residues produced hydrogen bonds with substrate when water molecules were not added to the system. The binding free energies also show differences. Overall, even the values of energy differences, but an implicit solvent provides the similar result (HPAI complex has higher activity than LPAI for both systems) in characterization of pathogenic virus neuraminidase activity.

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

A molecular dynamics simulation of two neuraminidase-sialic acid (NA-SA) complexes show a difference of the level of stability between sialic acid and neuraminidases that originated from viruses A/Tokyo/3/67 (Structure A) dan A/Pennsylvania/10218/84 (Structure B). Analyses of sialic acid RMSD and the change of torsional angles suggest that the sialic acid in Structure A is much more twisted and able to be influenced more by the binding of the neuraminidase functional residues than Structure B. Moreover, analyses upon hydrogen bond occupancy and binding free energy of both complexes showed that Structure A had more stable hydrogen bonds and each complex’s binding free energy were calculated to be –1.37 kcal/mol and 17.97 kcal/mol for Structure A and Structure B, respectively, further suggesting stability more dominant in Structure A than Structure B. Overall, Structure A has a more stable enzyme-substrate than Structure B.

Build mutant and build homology protein structure predictions for indonesian avian influenza neuraminidase

Protein structure modeling using a homologous template is one of many routines that accompany the molecular dynamics simulation for biological material. There are currently two protocols of protein modeling available in Accelrys Discovery Studio 2.1, Build Mutants and Build Homology Modeling protocols. Both are template-based modeling, but with a different process. In this study, two different templates, 3CKZ and 274Y, have been used to see how much the differences will be made by those two protocols if the templates has significant percentage of identity. Evaluation of structure models has been performed using DOPE score, 3D-profile, and PROCHECK. The results indicated that Build Mutants Protocols produces more stable structures but has a low reliability values and low quality of stereochemistry when using a template that has a lower percentage of identity. The results also yield more stable, reliable, and higher percentage of residues in most favoured and additionally allowed region for the usage of Build Homology Modeling Protocol on both templates. These observations suggest that Build Homology Modeling protocol is recommended for protein modeling.