Evolutionary and Functional Relationships in the Truncated Hemoglobin Family

Juan P. Bustamante, Leandro Radusky, Leonardo Boechi, Darío A. Estrin, Arjen ten Have, Marcelo A. Martí, Ozlem Keskin
2016 PLoS Computational Biology  
Predicting function from sequence is an important goal in current biological research, and although, broad functional assignment is possible when a protein is assigned to a family, predicting functional specificity with accuracy is not straightforward. If function is provided by key structural properties and the relevant properties can be computed using the sequence as the starting point, it should in principle be possible to predict function in detail. The truncated hemoglobin family presents
more » ... n interesting benchmark study due to their ubiquity, sequence diversity in the context of a conserved fold and the number of characterized members. Their functions are tightly related to O 2 affinity and reactivity, as determined by the association and dissociation rate constants, both of which can be predicted and analyzed using in-silico based tools. In the present work we have applied a strategy, which combines homology modeling with molecular based energy calculations, to predict and analyze function of all known truncated hemoglobins in an evolutionary context. Our results show that truncated hemoglobins present conserved family features, but that its structure is flexible enough to allow the switch from high to low affinity in a few evolutionary steps. Most proteins display moderate to high oxygen affinities and multiple ligand migration paths, which, besides some minor trends, show heterogeneous distributions throughout the phylogenetic tree, again suggesting fast functional adaptation. Our data not only deepens our comprehension of the structural basis governing ligand affinity, but they also highlight some interesting functional evolutionary trends. Author Summary Globins are a superfamily of widely studied and diverse globular proteins whose function is tightly related to their oxygen affinity and reactivity. Two prominent members are the well-known tetrameric hemoglobin and the monomeric myoglobin, both involved in reversible oxygen storage and transport in mammals. Truncated hemoglobins form one of PLOS Computational Biology | the three main monophyletic branches of this superfamily, presenting an interesting paradigm for structure-function prediction studies, as a result of their well-known and conserved fold. In the present work we started from the working hypothesis that states that "it is possible to predict the function starting solely from sequence information through the determination of structure based chemical reactivity patterns related to oxygen reactivity" and predicted oxygen reactivity for over 1000 truncated hemoglobins and analyzed the results in an evolutionary context. Our results taught us many interesting and novel features of these proteins, underscoring flexibility and adaptability of the globin fold. The work also shows that it is possible to characterize protein function in greater detail if specific sequence-to-function bridges are built upon a solid structural basis. Evolutionary and Functional Relationships in Globins PLOS Computational Biology |
doi:10.1371/journal.pcbi.1004701 pmid:26788940 pmcid:PMC4720485 fatcat:r7iesqio5zf5roxr3fqojw422m