Does the Composition of the Surrounding Solution Affect the Structure and Stability of the Protein Complex with a Ligand? A Molecular Dynamics Study

The 3D structure of proteins and protein–ligand complexes is determined by protein crystallography methods. In order to make the protein precipitate and prepare a complex, additional substances, including cosolvents, are added to the solution during the crystallization. However the presence of such additives can affect the structure of the protein and/or the complex, so that the XRD result will differ markedly from the structure of the complex in water and in physiological conditions. In the present study, we verify the presence of such influence on the example of a dimer of the SARS-Cov-2 main protease and a ligand exhibiting activity against SARS-CoV-2. An MD simulation of the complex in water and in 5% and 10% solutions of DMSO and dioxane in water is presented. It is shown that changes in the environment do not affect the structure of the protease dimer, but do significantly affect the interaction of the protein with the ligand. The sites of stable ligand bonding depend on the specific environment the complex is placed in. Thus, protein crystallography data should be treated very carefully: results obtained for one medium will not be necessarily true for another medium of a different composition.