Wild type (WT) and F185K mutant type of HIV-1 integrase catalytic domain (IN_C) were expressed and purified, and their solubility and activity were compared. The experiment results show that the solubility of F185K mutated IN_C was dramatically increased, whereas the activity was reduced to some extent. Subsequently, 1 800 ps molecular dynamics (MD) simulations for the WT and F185K type of IN_C in water were performed. The MD simulation results demonstrate that the flexibility of the catalytic loop region and the total mobility of F185K IN_C was reduced, which causes the decrease of activity. After the F185K mutation, changes of the salt bridge network drove the conformational change of IN_C, resulted in the burying of some hydrophobic residues and exposure of some other hydrophilic residues on the protein surface. Therefore, the relative hydrophilic solvent accessible surface of IN_C was increased. Moreover, the F185K mutation increased the hydrogen number between the IN_C protein and water molecule, as a consequence, the protein-water interaction was enhanced. These above changes contribute to the solubility increase of IN_C. It is found that the results obtained from MD simulation are in good agreement with the experiment data. The above mentioned results provides valuable insight for the understanding of protein solubility and will be helpful in protein engineering for increasing the solubility of proteins.