The physical chemical principles underlying,enzymatic thermostability are keys to understand the way evolution has shaped proteins,to adapt to a broad range of temperatures. Understanding the molecular determinants at the basis of protein thermostability is also important factor for engineering more thermoresistant enzymes to he used in the industrial-setting, such as, for instance, DNA, ligases, Which are important for DNA replication and repair and have been long used in molecular biology and biotechnology. Here, We fitst address the origin of thermostability in the thermophilic DNA ligase from archaeon Thermococcus sp. 1519 and identify thermosensitive regions using molecular modeling and simulations. In addition, we predict mutations that can enhance. thermostability of the enzyme through bioinformatics, analyses. We show that thermosensitive regions of this enzyme are stabilized at higher temperatures by optimization of charged groups on the surface, and we predict that thermostability can be further increased by further optimization of the network among these charged groups. Engineering this DNA ligase by introducing selected mutations (i.e., A287K, G304D, S364I, and A387K) eventually produced a significant and additive increase in the half-life of the enzyme when compared to that of the wild type.