Computational studies of protein stabilization and denaturation by small molecules

Proteins can have myriad interactions with other proteins and small molecules including water, which may have significant effects on the structure and dynamics of the protein. However, the properties of the solution environment of a protein are vastly simplified or even neglected in experimental and computational studies. Obtaining a complete perspective of the solvent forces on a protein at atomic resolution is not possible experimentally; therefore molecular dynamics simulations were used to study protein structure and dynamics in the presence of co-solvents and small molecules.; In this dissertation, the first three chapters discuss the development of co-solvent models for molecular dynamics simulations and application of these models. Chapters 1 and 2 discuss the development of co-solvent models for urea and trimethylamine n-oxide and the effects of these co-solvents on water structure and dynamics as well as interactions with model cyclic dipeptides within the framework of calorimetry experiments. Chapters 3 and 4 describe molecular dynamics simulations of barley chymotrypsin inhibitor 2 (CI2) in the presence of urea and TMAO, respectively.; The final two chapters add the dimension of possible therapeutic development to molecular dynamics simulations. Chapter 5 discusses the s-adenosylmethionine stabilization of catechol o-methyltransferase and ramifications of the Met108 mutation on structure and dynamics of the protein. Chapter b illustrates the potential protection of the natural fold of the prion protein under acidic conditions by TMAO. Data are also presented on possible re-conversion of a ‘scrapie-like’ structure of the prion protein in the presence of TMAO.