STRUCTURAL BIOINFORMATICS: A WINDOW TO OBSERVE THE PROTEIN UNIVERSE

Analyzing huge amounts of data that are stored in biologically relevant databases to find information to be translated into new general knowledge, is the essence of Bioinformatics. During my PhD training, have implemented Structural Bioinformatics procedures to derive information from the wealth of structural data that is publically available from the Protein Data Bank. From the thousands of experimentally derived structures where proteins are bound to other proteins, nucleic acids or small organic molecules, We found signals for interpreting the rationale underneath Nature’s assignment of codon multiplicity. The fact that arginine appeared as the most common amino acid at protein-nucleic acid interfaces, not only explained the reason why the latter amino acids has six different codons, in spite of its average occurrence in proteins [Gardini S, Cheli S, Baroni S, Di Lascio G, Mangiavacchi G, Micheletti N, Monaco CL, Savini L, Alocci D, Mangani S, Niccolai N. On Nature's Strategy for Assigning Genetic Code Multiplicity. PLoS One. 2016 Feb 5;11(2):e0148174], but also suggested possible roles of natural amino acids to determine specific dynamics of protein-protein and protein-nucleic acid interactions. I investigated in details the dynamics of protein-DNA approaches, by analysing amino acid occurrence at protein-DNA interfaces in a series of refined PDB files. The presence of negatively charged side chains of aspartate and glutamate at the protein-DNA interface was observed in a large majority of DNA complexes with enzymes such as polymerases, helicases, topoisomerases etc., that is in all those structures related to systems requiring a very dynamic intermolecular approach. Whenever a more static protein-DNA is needed, for instance in the case of histons, the largest presence of interfacial arginines is found to ensure sticky interactions between its guanidine side chains with DNA phosphate backbone groups. Transcription factors, interestingly, exhibited an intermediate behaviour [Gardini S, Furini S, Santucci A, Niccolai N. A structural bioinformatics investigation on protein-DNA complexes delineates their modes of interaction. Mol Biosyst. 2017 May 2;13(5):1010-1017]. The latter results, having an extreme relevance in possible biotechnological applications, stimulated Gardini to test, with computational and experimental procedures, the validity of his hypothesis. This activity has been carried out in Prof. Matteo Dal Peraro’s lab in Losanna and in Prof. Annalisa Pastore’s lab in London. He tried to use Molecular Dynamics simulations by using the computational facilities of the Swiss lab to confirm how Arg/Lys replacements could modulate protein sliding along DNA rails. In London, he tried to engineer amino acid mutations on model systems of DNA related enzymes. Both investigations will require additional time, as in the three months spent both in Switzerland and United Kingdom, he could not achieve unambiguous results. A third Structural Bioinformatics project is now close to its completion that is to find messages in protein core compositions, which can determine specific protein folding. In this respect, encouraging results have been obtained and a manuscript is in preparation.