1Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Campus E1 4, Saarbrücken 66123, Germany,2Graduate School for Computer Science, Saarland University, Campus E1 3, Saarbrücken 66123, Germany,3Department of Computer Science and Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA 01609, USA
Checking for direct PDF access through Ovid
Motivation: Due to their high genomic variability, RNA viruses and retroviruses present a unique opportunity for detailed study of molecular evolution. Lentiviruses, with HIV being a notable example, are one of the best studied viral groups: hundreds of thousands of sequences are available together with experimentally resolved three-dimensional structures for most viral proteins. In this work, we use these data to study specific patterns of evolution of the viral proteins, and their relationship to protein interactions and immunogenicity.Results: We propose a method for identification of two types of surface residues clusters with abnormal conservation: extremely conserved and extremely variable clusters. We identify them on the surface of proteins from HIV and other animal immunodeficiency viruses. Both types of clusters are overrepresented on the interaction interfaces of viral proteins with other proteins, nucleic acids or low molecular-weight ligands, both in the viral particle and between the virus and its host. In the immunodeficiency viruses, the interaction interfaces are not more conserved than the corresponding proteins on an average, and we show that extremely conserved clusters coincide with protein–protein interaction hotspots, predicted as the residues with the largest energetic contribution to the interaction. Extremely variable clusters have been identified here for the first time. In the HIV-1 envelope protein gp120, they overlap with known antigenic sites. These antigenic sites also contain many residues from extremely conserved clusters, hence representing a unique interacting interface enriched both in extremely conserved and in extremely variable clusters of residues. This observation may have important implication for antiretroviral vaccine development.Availability and Implementation: A Python package is available at https://bioinf.mpi-inf.mpg.de/publications/viral-ppi-pred/Contact:email@example.com or firstname.lastname@example.orgSupplementary information: Supplementary data are available at Bioinformatics online.