EXPLORING THE ROLE OF THE SOLVENT IN THE DENATURATION OF A PROTEIN - A MOLECULAR-DYNAMICS STUDY OF THE DNA-BINDING DOMAIN OF THE 434-REPRESSOR

Molecular dynamics simulations of the DNA binding domain of 434 repres sor are presented which aim at unraveling the role of solvent in prote in denaturation. Four altered solvent models, each mimicking various p ossible aspects of the addition of a denaturant to the aqueous solvent , were used in the simulations to analyze their effects on the stabili ty of the protein. The solvent was altered by selectively changing the Coulombic interaction between water and protein atoms and between dif ferent water molecules. The use of a modified solvent model has the ad vantage of mimicking the presence of denaturant without having denatur ant molecules present in the simulation, which would require much long er simulations. In these simulations, only an increase in the solvent- protein Coulombic interaction causes initiation of protein unfolding i n a manner consistent with NMR data. The altered solvent thus provides a model of a denaturing environment for studying protein unfolding.