Impact of non synonymous single nucleotide variants on protein fitness: experimental analysis for a comparative study

Proteins are large biological molecules that control most vital cellular functions. They consist of one or more chains of amino acids in an order determined by the base sequence of nucleotides in the DNA coding for the protein. Thanks to the information from the genetic code and according to the energy landscape, proteins fold into their correct three-dimensional structures and exert their specific function. The correct fold of large portion of the structure is generally related to specific protein functions and when any even small alterations occur, it is possible to observe a decrease, an increase or a drastic change in the protein function. In several cases alterations at the amino acid level can influence the conformational rearrangement, the function or the binding properties of a given protein. On this premise, knowledge on protein structure-function relationships can be crucial in finding the molecular basis for hereditary diseases and in predicting protein function from structure and vice versa. Therefore, the study of structure-function relationships is really important nowadays to better understand several diseases at their molecular level. In particular, this kind of approach seems to be relevant in cancer research considering that several somatic variants resulting from alterations at the amino acid level have been detected in cancer genome for several proteins. The analysis of this kind of alterations is key to understand the genetic bases of disease progression, patient survival and also response to therapy. Since knowledge of protein function in health and disease is essential to identify new and more specific cures for different diseases and to design pharmacologically active and more selective drugs, the information resulting from the analysis of somatic mutations found in cancer tissues can improve the available therapies and create new and more specific ones suggesting that precision and personalized medicine is not anymore a daydream.