Mauro Colafranceschi

Haemoglobin polymorphisms affect the oxygen- binding properties in Atlantic cod populations

A major challenge in evolutionary biology is to identify the genes underlying adaptation. The oxygen-transporting haemoglobins directly link external conditions with metabolic needs and therefore represent a unique system for studying environmental effects on molecular evolution. We have discovered two haemoglobin polymorphisms in Atlantic cod populations inhabiting varying temperature and oxygen regimes in the North Atlantic. Three-dimensional modelling of the tetrameric haemoglobin structure demonstrated that the two amino acid replacements Met55β1Val and Lys62β1Ala are located at crucial positions of the α1β1 subunit interface and haem pocket, respectively. The replacements are proposed to affect the oxygen-binding properties by modifying the haemoglobin quaternary structure and electrostatic feature. Intriguingly, the same molecular mechanism for facilitating oxygen binding is found in avian species adapted to high altitudes, illustrating convergent evolution in water- and air-breathing vertebrates to reduction in environmental oxygen availability. Cod populations inhabiting the cold Arctic waters and the low-oxygen Baltic Sea seem well adapted to these conditions by possessing the high oxygen affinity Val55–Ala62 haplotype, while the temperature-insensitive Met55–Lys62 haplotype predominates in the southern populations. The distinct distributions of the functionally different haemoglobin variants indicate that the present biogeography of this ecologically and economically important species might be seriously affected by global warming.

Protein Aggregation/Folding: The Role of Deterministic Singularities of Sequence Hydrophobicity as Determined by Nonlinear Signal Analysis of Acylphosphatase and Aβ(1–40)

The problem of protein folding vs. aggregation was investigated in acylphosphatase and the amyloid protein Abeta(1-40) by means of nonlinear signal analysis of their chain hydrophobicity. Numerical descriptors of recurrence patterns provided the basis for statistical evaluation of folding/aggregation distinctive features. Static and dynamic approaches were used to elucidate conditions coincident with folding vs. aggregation using comparisons with known protein secondary structure classifications, site-directed mutagenesis studies of acylphosphatase, and molecular dynamics simulations of amyloid protein, Abeta(1-40). The results suggest that a feature derived from principal component space characterized by the smoothness of singular, deterministic hydrophobicity patches plays a significant role in the conditions governing protein aggregation.

Entropic criteria for protein folding derived from recurrences: Six residues patch as the basic protein word

Some research has suggested that patches of six constitute an important amino acid window length in proteins for conveying information. We present database evidence that supports this conjecture, as well as additional recurrence‐based data that characterization and quantification of these words affect the folding/aggregation features of proteins. Other indirect evidence is presented and discussed.

Large contact surface interactions between proteins detected by time series analysis methods: case study on C-phycocyanins.

A purely sequence‐dependent approach to the modeling of protein–protein interaction was applied to the study of C‐phycocyanin αβ dimers. The interacting pairs (α and β subunits) share an almost complete structural homology, together with a general lack of sequence superposition; thus, they constitute a particularly relevant example for protein–protein interaction prediction. The present analysis is based on a description posited at an intermediate level between sequence and structure, that is, the hydrophobicity patterning along the chains. Based on the description of the sequence hydrophobicity patterns through a battery of nonlinear tools (recurrence quantification analysis and other sequence complexity descriptors), we were able to generate an explicit equation modeling α and β monomers interaction; the model consisted of canonical correlation between the hydrophobicity autocorrelation structures of the interacting pairs. The general implications of this holistic approach to the modeling of protein–protein interactions, which considers the protein primary structures as a whole, are discussed. Proteins 2003;51:299–310.

Simulated Point Mutations in the Aα-Chain of Human Fibrinogen Support a Role of the αC Domain in the Stabilization of Fibrin Gel

The hydrophobicity pattern distribution in the Aα-, Bβ- and γ-chains of human fibrinogen has been studied by a nonlinear method, recurrence quantification analysis, in the wild type and in a number of naturally occurring or simulated mutants. The aim was to find a structural basis for distinguishing between silent and pathological mutants. We were successful in the case of mutations on the Aα-chain, thanks to the peculiar features of this chain as compared to the other two. Relevant findings concerning the point mutants of the Aα-chain are the following: (a) the recurrence quantification analysis-based classification of such mutants is in good agreement with the clinical classification, and (b) the location of the mutated residue on the sequence plays a more relevant role than its hydrophobic features. Artificial point mutants in the terminal zone (600–866 residues) of the extended isoform of the Aα-chain cluster together with the natural hemorrhagic mutants of the first (1–207) residues.

Hydrophobicity patterns and biological adaptation: an exemplary case from fish hemoglobins.

The dissection of phylogenetic and environmental components in biological evolution is one of the main themes of general biology. Here we propose an approach to this theme relying upon the comparison between a phylogenetic oriented metrics spanning the hemoglobin beta chains of different fishes and a more physiologically oriented metrics defining the same sequences in terms of the dynamical features of their hydrophobic distributions. By analyzing the set of sequences more similar to the Gadus morhua (Atlantic cod) hemoglobin beta chain, we were able to give a proof of concept of the possibility to discriminate the phylogenetic and environmental (evolutive convergence) components by the comparative analysis of the Clustal W (phylogenetics first) and Recurrence Quantification Analysis (physiology first) metrics in which the sequences were embedded. The use of a molecular system like hemoglobin playing a crucial role in fishes adaptation to environmental cues allowed us to span different levels of biological variability by means of the same paradigm. Starting from the reconstruction of the general taxonomy of vertebrate groups we went down to the exploitation of the peculiar role played by Met55Val and Lys62Ala polymorphisms in the beta1 hemoglobin chain of the Atlantic cod able to influence the geographical distribution of its various stocks.