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A Look Inside HIV Resistance through Retroviral Protease Interaction Maps 1,2 1 1 1 1 1 Aleksejs Kontijevskis , Peteris Prusis , Ramona Petrovska , Sviatlana Yahorava , Felikss Mutulis , Ilze Mutule , 2 1* Jan Komorowski , Jarl E. S. Wikberg 1 Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, 2 Linnaeus Centre for Bioinformatics, Uppsala University, Uppsala, Sweden Retroviruses affect a large number of species, from fish and birds to mammals and humans, with global socioeconomic negative impacts. Here the authors report and experimentally validate a novel approach for the analysis of the molecular networks that are involved in the recognition of substrates by retroviral proteases. Using multivariate analysis of the sequence-based physiochemical descriptions of 61 retroviral proteases comprising wild-type proteases, natural mutants, and drug-resistant forms of proteases from nine different viral species in relation to their ability to cleave 299 substrates, the authors mapped the physicochemical properties and cross-dependencies of the amino acids of the proteases and their substrates, which revealed a complex molecular interaction network of substrate recognition and cleavage. The approach allowed a detailed analysis of the molecular–chemical mechanisms involved in substrate cleavage by retroviral proteases. Citation: Kontijevskis A, Prusis P, Petrovska R, Yahorava S, Mutulis F, et al. (2007) A look inside HIV resistance through retroviral protease interaction maps. PLoS Comput Biol 3(3): e48. doi:10.1371/journal.pcbi.0030048 Introduction validation of a novel strategy for the molecular analysis of