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Plasticity of 150-loop in influenza neuraminidase explored by Hamiltonian replica exchange molecular dynamics
1School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
Abstract:
Neuraminidase (NA) of influenza is a key target for antiviral inhibitors, and the 150-cavity in group-1 NA provides new insight in treating this disease. However, NA of 2009 pandemic influenza (09N1) was found lacking this cavity in a crystal structure. To address the issue of flexibility of the 150-loop, Hamiltonian replica exchange molecular dynamics simulations were performed on different groups of NAs. Free energy landscape calculated based on the volume of 150-cavity indicates that 09N1 prefers open forms of 150-loop. The turn A (residues 147-150) of the 150-loop is discovered as the most dynamical motif which induces the inter-conversion of this loop among different conformations. In the turn A, the backbone dynamic of residue 149 is highly related with the shape of 150-loop, thus can function as a marker for the conformation of 150-loop. As a contrast, the closed conformation of 150-loop is more energetically favorable in N2, one of group-2 NAs. The D147-H150 salt bridge is found having no correlation with the conformation of 150-loop. Instead the intimate salt bridge interaction between the 150 and 430 loops in N2 variant contributes the stabilizing factor for the closed form of 150-loop. The clustering analysis elaborates the structural plasticity of the loop. This enhanced sampling simulation provides more information in further structural-based drug discovery on influenza virus.
Insights
Influenza neuraminidase (NA) flexibility was studied using molecular dynamics. The 2009 pandemic NA favors open 150-loop conformations, unlike N2 which prefers closed forms, offering insights for antiviral drug discovery.
Area of Science:
- Virology
- Structural Biology
- Computational Chemistry
Background:
- Neuraminidase (NA) is a crucial target for influenza antiviral drugs.
- The 150-cavity in group-1 NA is important for inhibitor binding.
- The 2009 pandemic influenza NA (09N1) lacks this cavity in crystal structures, raising questions about loop flexibility.
Purpose of the Study:
- To investigate the conformational flexibility of the NA 150-loop in different influenza strains.
- To understand the factors governing the open and closed conformations of the 150-loop.
- To provide insights for structure-based drug discovery targeting influenza NA.
Main Methods:
- Hamiltonian replica exchange molecular dynamics simulations were employed.
- Free energy landscapes were calculated based on 150-cavity volume.
- Clustering analysis was used to study loop structural plasticity.
Main Results:
- The 09N1 NA preferentially adopts open 150-loop conformations.
- Turn A (residues 147-150) is the most dynamic motif, with residue 149's dynamics correlating with loop shape.
- Group-2 N2 NA favors a closed 150-loop conformation, stabilized by interactions between the 150 and 430 loops.
Conclusions:
- The 150-loop exhibits significant structural plasticity, with strain-dependent conformational preferences.
- Residue 149 in Turn A can serve as a marker for 150-loop conformation.
- Understanding these dynamics is vital for developing effective influenza antiviral inhibitors.
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