Abstract
BackgroundInfluenza A viruses possess RNA genomes that mutate frequently in response to immune pressures. The mutations in the hemagglutinin genes are particularly significant, as the hemagglutinin proteins mediate attachment and fusion to host cells, thereby influencing viral pathogenicity and species specificity. Large-scale influenza A genome sequencing efforts have been ongoing to understand past epidemics and pandemics and anticipate future outbreaks. Sequencing efforts thus far have generated nearly 9,000 distinct hemagglutinin amino acid sequences.DescriptionComparative models for all publicly available influenza A hemagglutinin protein sequences (8,769 to date) were generated using the Rosetta modeling suite. The C-alpha root mean square deviations between a randomly chosen test set of models and their crystallographic templates were less than 2 Å, suggesting that the modeling protocols yielded high-quality results. The models were compiled into an online resource, the Hemagglutinin Structure Prediction (HASP) server. The HASP server was designed as a scientific tool for researchers to visualize hemagglutinin protein sequences of interest in a three-dimensional context. With a built-in molecular viewer, hemagglutinin models can be compared side-by-side and navigated by a corresponding sequence alignment. The models and alignments can be downloaded for offline use and further analysis.ConclusionsThe modeling protocols used in the HASP server scale well for large amounts of sequences and will keep pace with expanded sequencing efforts. The conservative approach to modeling and the intuitive search and visualization interfaces allow researchers to quickly analyze hemagglutinin sequences of interest in the context of the most highly related experimental structures, and allow them to directly compare hemagglutinin sequences to each other simultaneously in their two- and three-dimensional contexts. The models and methodology have shown utility in current research efforts and the ongoing aim of the HASP server is to continue to accelerate influenza A research and have a positive impact on global public health.
Highlights
Influenza A viruses possess RNA genomes that mutate frequently in response to immune pressures
The modeling protocols used in the Hemagglutinin Structure Prediction (HASP) server scale well for large amounts of sequences and will keep pace with expanded sequencing efforts
Information provided for each sequence includes the EMBL ID, Discussion of HASP server use through a case study In the World Health Organization’s Human Animal Interface online database for H5N1 Avian Influenza in Humans, it is reported that there were three deaths from H5N1 in Vietnam in 2003 and twenty deaths in 2004 [14]
Summary
Because HA regulates IAV entry into the cell [15] and strongly impacts both pathogenicity and interspecies. The HASP server was designed to enable researchers to visualize their HA sequences of interest in the three-dimensional context of the most related HA crystal structure It employs computationally fast protocols for model generation, database navigation, and visualization appropriate for the large number of HA sequences and scalable with increasing sequence data. The primary aim of the HASP server is to provide a tool for viewing and comparing amino acid changes in HA subtypes at all levels of protein structure, from primary to quaternary, giving a complete and integrated view of those changes to facilitate understanding Understanding these changes, which determine the efficiency of transmission, pathology, and ecology of these viruses, is of critical and vital importance to global public health. All authors contributed to and edited the manuscript, and approved the final version
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