Improved insights into protein thermal stability: from the molecular to the structurome scale

Despite the intense efforts of the last decades to understand the thermal stability of proteins, the mechanisms responsible for its modulation still remain debated. In this investigation, we tackle this issue by showing how a multi-scale perspective can yield new insights. With the help of temperature-dependent statistical potentials, we analyzed some amino acid interactions at the molecular level, which are suggested to be relevant for the enhancement of thermal resistance. We then investigated the thermal stability at the protein level by quantifying its modification upon amino acid substitutions. Finally, a large scale analysis of protein stability - at the structurome level - contributed to the clarification of the relation between stability and natural evolution, thereby showing that the mutational profile of thermostable and mesostable proteins differ. Some final considerations on how the multi-scale approach could help unraveling the protein stability mechanisms are briefly discussed.