Plasticity of 150-loop in influenza neuraminidase explored by Hamiltonian replica exchange molecular dynamics simulations

• Published in: PloS one 2013-04, Vol.8 (4), p.e60995-e60995
• Main Authors: Han, Nanyu, Mu, Yuguang
• Format: Article
• Language: English
• Subjects: Analysis; Antiviral agents; Biology; Chemistry; Cluster Analysis; Clustering; Computer Science; Conformation; Crystal structure; Drug discovery; Drugs; Energy; Epidemics; Exo-a-sialidase; Free energy; Influenza; Influenza A virus - enzymology; Influenza viruses; Medicine; Molecular dynamics; Molecular Dynamics Simulation; Mutation; Neuraminidase - chemistry; Neuraminidase - metabolism; Pandemics; Physics; Plastic properties; Plasticity; Principal components analysis; Protein Conformation; Proteins; Salts; Simulation; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060995

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.